Psychedelics and Depression

Psychedelics and depression is one of the 'psychedelics and ...' topics that we're currently making a page for. At this moment you can find all papers (in our database) on this topic below.

Research Papers Compared Measured Researchers Gaps Companies

State of Research


Quality of Conclusions


Data Points

TBD Papers studying this directly
TBD Companies working on this

Access all our research

Become a free member now to get unlimited access.

Receive our weekly update on the latest psychedelic research, make (private) notes on pages, and download our reports.

Our vision is that psychedelics can be used worldwide to better the lives of as many as 450 million people who suffer from mental health problems. Our information hopes to make that vision come to life just a little faster.

Depression Research

Here will be a narrative, readable, summary of the research.


In our literature study we came across the following studies of note. Browse the meta, review, commentary articles for an overview. Check out the individual studies for specific experiments and observations.

Assessing the effects of methodological differences on outcomes in the use of psychedelics in the treatment of anxiety and depressive disorders: A systematic review and meta-analysis

2021 | Lang, R. F., Leger, R. F., Unterwald, E. M.

This review paper (2021) explored the type of psychedelics used across a number of studies and the number of dosing sessions administered that affect subjects’ depression and anxiety outcomes and adverse drug reactions. The authors conclude that psilocybin, ayahuasca & DMT all appear to be effective and safe in improving symptoms of anxiety and depression.

Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review

2021 | Alfonso, M., Jahan, N., Khurshid, H., Qureshi, I. A., Sapkota, A., Sultan, W., Went, T. R.

This review (2021, s=10) finds that only one of three short-term studies found favourable effects of esketamine over only antidepressants for depression, but other studies did find longer time to relapse or a longer sustained improvement in depressive symptoms.

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

2015 | Carpenter, L. L., McDonald, W., Nemeroff, C. B., Newport, D. J., Potash, J. B., Tohen, M.

This systematic review (2015) and meta-analysis (n=147) investigates ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression. It highlighted the antidepressant efficacy of ketamine, and D-cycloserine and rapastinel for future glutamate-modulating strategies but also noted the ineffectiveness of other NMDA antagonists. It underlined the need for a greater understanding of ketamine’s mechanism of action.

Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior

2021 | Canuso, C. M., Fu, D. J., Ionescu, D. F., Lane, R., Li, X., Lopena, T. J., Nash, A. I., Qui, X., Turkoz, I.

This pooled analysis (n=456) of the two ASPIRE studies (comparing ketamine to placebo, both with standard care) finds significant improvements in depression scores immediately (4 & 24 hours) up to 25 days later (all similar reductions). The study also showed improvements on suicidal ideation (which all patients had), most for those with a history of suicide attempt.

Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature

2017 | Grady, S. E., Klein, K., Marsh, T. A., Tenhouse, A.

This literature review (2017) of randomized, placebo-controlled trials explores the effects of ketamine in treatment-resistant depression (TRD) and bipolar depression (BD). Ketamine reduced symptoms in both and is a promising compound for those who have found other treatments lacking.

Ketamine Treatment for Depression in Patients With a History of Psychosis or Current Psychotic Symptoms: A Systematic Review

2021 | Kamphuis, J., Schoevers, R. A., Smith-Apeldoorn, S. Y., Spijker, J., Veraart, J. K. E.

This systematic review (2021) examines whether ketamine treatment in patients with a history of psychosis or current psychotic symptoms and found 9 pilot studies (n=41) which indicate that ketamine's side effects are mild and self-limiting even among these patients. While limited in sample size, the available literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients.

Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders

2017 | Lastra, D., Malcolm, B., Thomas, K.

This 2017 review examines studies on psilocybin-assisted therapy to treat psychiatric disorders related to depression, anxiety, and substance abuse. In contrast to conventional paradigms, psilocybin-assisted therapy consists of only a few six-hour medication therapy sessions that may significantly improve symptoms and help patients achieve response or remission within weeks with support from integrative psychotherapy sessions.

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

2015 | Ionescu, D. F., Papakostas, G. I.

This review (2015) discusses research developments regarding therapeutic compounds that exert their antidepressant efficacy via the glutamatergic, cholinergic, and opioid systems. The authors encourage innovative research strategies for improving the efficacy of treatments such as ketamine, whose effects are rapid but not long-lasting.

Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression

2015 | Choucha, W., Fossati, P., Romeo, B., Rotge, J.

This meta-analysis (2015) of six randomized, double-blind, placebo-controlled trials (n=101) examined the short-and mid-term efficacy of ketamine (bipolar) to depression. Ketamine effectively reduced symptoms in unipolar depression for seven days, , whereas the maintenance of its efficacy in bipolar depression failed to reach significance after 4 days.

New Treatment Strategies of Depression: Based on Mechanisms Related to Neuroplasticity

2017 | Huang, Y. J., Lane, H. Y., Lin, C. H.

This review (2017) examines treatment strategies for depression based on neuroplasticity induction via non-invasive brain stimulation and NMDA receptor and glutamatergic modulation via ketamine. The authors raise concerns over the long-term antidepressive efficacy and safety of ketamine and highlight other MDA receptor and glutamate modulators, such as sarcosine, which show antidepressive effects in small-scale studies.

Do sleep changes mediate the anti-depressive and anti-suicidal response of intravenous ketamine in treatment-resistant depression?

2021 | Cao, B., Cha, D. S., Cubała, W. J., Gill, H., Ho, R., Kratiuk, K., Lee, Y., Lipsitz, O., Lui, L. M. W., Mansur, R. B., McIntyre, R. S., Rodrigues, N. B., Rosenblat, J. D., Shekotikhina, M., Subramaniapillai, M., Teopiz, K. M.

This open-label study (n=323) with repeated IV ketamine infusions (4x, 35mg/70kg) finds that sleep is a partial mediator to the improvements in depression (TRD), similar effects were found on reducing suicidal ideation (SI).

Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review

2021 | Bakker, I. M., Kamphuis, J., Schoevers, R. A., Smith-Apeldoorn, S. Y., Touw, D. J., Veraart, J. K. E., Visser, B. A. E.

This systematic review (2021) examines the pharmacodynamic interactions between ketamine and generally prescribed psychiatric drugs based on published evidence and found that lamotrigine and benzodiazepines attenuate and shorten ketamine’s antidepressant effects. There are also indications for interactions between ketamine and antipsychotic drugs, such as haloperidol, risperidone and clozapine (but not olanzapine), although further research is necessary to understand their side effects.

Psychedelic Psychiatry’s Brave New World

2020 | Carhart-Harris, R. L., Erritzoe, D., Nutt, D. J.

This popular commentary article (2020) describes the current resurrection of research into psychedelics (both neuroscience and therapeutic applications). It describes the evidence for the serotonin receptor (5-HT2a) agonism (psychedelics binding to that receptor) and the possible mechanisms through which long-lasting therapeutic effects can be found.

Ketamine's effect on inflammation and kynurenine pathway in depression: A systematic review

2021 | Kopra, E., Mondelli, V., Nikkheslat, N., Pariante, C.

This literature review (2021) explores ketamine's anti-inflammatory properties and tryptophan-kynurenine (KYN) pathway in patients with unipolar and bipolar depression as well as in animal models of depression. It found that ketamine induces anti-inflammatory effects in at least a proportion of patients with depression and decreased activation of the KYN pathway's neurotoxic arm.

Natural Psychoplastogens As Antidepressant Agents

2020 | Benko, J., Vranková, S.

This review (2020) explored recent advances in natural psychoplastogens (psychedelics) as antidepressant agents. The study noted that these compounds are effective in rapid structural and functional rearrangement of neural systems by targeting mechanisms that were previously implicated in the development of depression. The study observed the evidence that they expend potent acute and long-term positive effects, beyond the treatment of psychiatric disorders with many of them being naturally occurring compounds, like psilocybin and DMT.

Intranasal Ketamine for Depression in Adults: A Systematic Review and Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials

2021 | An, D., Wang, J., Wei, C., Wu, A.

This meta-analysis (s=6, n=858) found that (es)ketamine administrated intranasally (via the nose) led to quick antidepressant effects for those suffering from depression (MDD & TRD). Although the effect was most pronounced in the first 24 hours after administration (MADRS decreased by 9.96 points), the effects held up at 28 days (4.09).

Psilocybin and MDMA for the treatment of trauma-related psychopathology

2021 | Bird, C. I. V., Modlin, N. L., Rucker, J.

This review (2021) investigates the therapeutic rationale behind the use of psilocybin and MDMA in the treatment of PTSD and depression. Both compounds and the possible treatment modalities (the combination with talk therapy) are discussed. A combination of first MDMA-assisted therapy, followed by psilocybin-assisted therapy is also presented.

A unique natural selective kappa-opioid receptor agonist, salvinorin A, and its roles in human therapeutics

2017 | Cruz, A. P. M., Domingos, S., Gallardo, E., Martinho, A.

This review (2016) examines the psychoactive properties and therapeutic potential of Salvinorin A, a kappa-opioid receptor agonist that is the bioactive constituent of the indigenous plant Salvia divinorum. Next to highly potent psychoactive properties as a dissociative hallucinogen, preliminary scientific evidence also indicates it may have broad-range therapeutic applications for treating addiction, inflammation, pain, and depression.

Psychedelic Medicines in Major Depression: Progress and Future Challenges

2021 | Bouso, J. C., Dos Santos, R. G., Hallak, J. E., Ona, G.

This book chapter (2021) describes the current research on psychedelics for depression (MDD), the clinical trials as well as the neurobiological mechanisms are described. The chapter end with a description of future challenges.

Therapeutic use of classic psychedelics to treat cancer-related psychiatric distress

2018 | Ross, S.

This systematic review (2018) investigated studies that used psychedelics for the treatment of psychological distress related to cancer. It found 10 studies (n=445) that qualified of which four (n=104) were randomized controlled trials. Overall studies showed improvements in anxiety, depression, and fear of death.

Registered clinical studies investigating psychedelic drugs for psychiatric disorders

2021 | Gill, H., Lipsitz, O., Lui, L. M. W., McIntyre, R. S., Rosenblat, J. D., Siegel, A. N., Teopiz, K. M.

This review (2021) summarizes the study characteristics of all ongoing registered clinical trials investigating psychedelic drugs for psychiatric disorders and identifies that their majority focuses on investigating MDMA and psilocybin for treating depression or PTSD, while only 30% of their results are published.

Sex differences in sub-anesthetic ketamine’s antidepressant effects and abuse liability

2018 | Kabbaj, M., Wright, K. N.

This review (2018) examines gender-related differences related to antidepressant effects and abuse liability of ketamine given that women are twice as likely to develop depression and progress through the stages of addiction faster than men. Preclinical evidence suggests that female rats are indeed more sensitive to ketamine’s effects, but more clinical research is needed to verify these gender-related effects in humans.

Improving cognitive functioning in major depressive disorder with psychedelics: a dimensional approach

2021 | Kuiperes, Z., Magaraggia, I, Schreiber, R.

This theory-building literature review (2021) proposes a model that explains how psychedelics can reduce the negativity bias in depressed patients according to Research Domain Criteria (RDoC), a framework that investigates the underlying neurobiology of clinical symptoms across multiple levels of explanation. It is proposed that psychedelics improve depressive symptoms via a similar mechanism as the antidepressant vortioxetine, by stimulating neuroplasticity in the prefrontal cortex and the hippocampus, and decreasing negativity bias through the restoration of deficits in pattern separation.

Production Options for Psilocybin: Making of the Magic

2018 | Blei, F., Fricke, J., Hoffmeister, D., Lenz, C., Wick, J.

This historic review (2019) examines the biosynthesis and pharmacology of psilocybin, and summarizes the biotechnological routes of its synthesis.

Decreased brain modularity after psilocybin therapy for depression

2021 | Carhart-Harris, R. L., Daws, R. E., Erritzoe, D., Giribaldi, B., Nutt, D. J., Roseman, L., Sexton, J. D., Timmermann, C., Wall, M.

This preprint (2021) analyzed data from an open-label (n=16) and a randomized double-blind placebo-controlled study (n=43) of psilocybin (10 - 25mg) treatment for depression, in order to identify neural biomarkers underlying antidepressant efficacy. Psilocybin (but not escitalopram) decreased brain modularity across both trials, i.e. brain connectivity became less segregated, and this correlated with improvements in depressive symptomatology.

Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

2018 | Brietzke, E., Cha, D. S., Fus, D., Lee, Y. L., Lui, L. M. W., Mansur, R. B., McIntyre, R. S., Pan, Z., Park, C., Rong, C., Rosenblat, J. D., Subramaniapillai, M., Zuckerman, H.

This meta-analysis (2018) examined whether clinical and biological pretreatment variables could predict the treatment response of ketamine for patients with (bipolar) depression, but found that its antidepressant efficacy was highly variable and did not depend on any single predictor, although certain inflammatory biomarkers were associated with a positive response.

Future Directions for Clinical Psychedelic Research: The Relaxed Symptom Network

2021 | Laukkonen, R., Lewis-Healey, E., van Elk, M.

This preprint (2021) extends the methodological framework for investigating the efficacy of psychedelic-assisted therapy by reconceptualizing mental health disorders as an emergent property of psychological, biological, and societal symptom networks which reinforce self-sustained patterns of psychopathology. It is hypothesized that psychedelic-assisted psychotherapy can make people more resilient against depression by weakening the network connections between symptoms and disrupting negative feedback of maladaptive patterns.

Blood d-serine levels as a predictive biomarker for the rapid antidepressant effects of the NMDA receptor antagonist ketamine

2015 | Hashimoto, K.

This letter to the editor proposes blood d-serine levels as a predictive biomarker for the effects of ketamine.

Ketamine administration in depressive disorders: a systematic review and meta-analysis

2014 | Abbar, M., Boyer, L., Brittner, M., Courtet, P., Fond, G., Lançon, C., Leboyer, M., Loundou, A., Macgregor, A., Micoulaud-Franchi, J., Rabu, C., Richieri, R., Roger, M.

This review (2015, n=118) found that ketamine showed reliable anti-depressive effects in patients diagnosed with either MDD or bipolar disorder (BD). The duration of effects, however, requires further research.

The role of ketamine in treatment-resistant depression: a systematic review

2014 | Amore, M., Girardi, P., Howland, R. H., Rovedi, F., Serafini, G.

This review (24 studies; n=416) found that ketamine is a reliable fast-acting anti-depressant for patients suffering from treatment-resistant depression (TRD). Long-term effects, however, remain to be studied.

Side-effects associated with ketamine use in depression: a systematic review

2017 | Fong, J., Galvez, V., Loo, C., Shelker, W., Short, B.

This systematic review (2017) examined the reported side-effects of ketamine treatment for depression across 288 published reports and identified that headache, dizziness, dissociation, elevated blood pressure, and blurred vision were the most common in response to intravenous infusion. The most common acute psychiatric side-effect was anxiety, but there was no conclusive evidence about long-term side effects from the currently available studies.

Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?

2017 | Andrade, C.

This qualitative review and meta-analysis (2017) summarizes major insights on the antidepressant efficacy of ketamine studies, with respect to differences across dosing, rate of administration, route of administration, duration of treatment, and frequency of sessions. It found that there is not enough supporting evidence to draw conclusions about best practices based on how these parameters interact with one another.

Ketamine and other potential glutamate antidepressants

2014 | Deakin, J. F. W., Dutta, A., McKie, S.

This review (2015) examined molecular mechanisms underlying the antidepressant efficacy of ketamine and other glutamate drugs in humans. Although antidepressant effects are partially mediated through glutamate release onto non-NMDA receptors including AMPA and metabotropic receptors, there are also reported effects on 5-HT, dopamine, and intracellular effects on the mTOR pathway in animal studies that are yet to be elucidated.

Psychedelic Drugs in Biomedicine

2017 | Gainetdinov, R. R., Kalueff, A. V., Kyzar, E. J., Nichols, C. D., Nichols, D. E.

This review (2017) summarizes pre/clinical data pertaining to the effects of psychedelics and their pharmacological mechanisms of action and outlines future areas of translational research to investigate how synapse-related gene expression influences the disruption of established neural connectivity patterns, underlying therapeutic effects.

Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

2021 | Sanacora, G., Schatzberg, A. F.

This commentary review (2014) highlights the strength of evidence from recent proof-of-concept studies of ketamine which bear promise for the rapid treatment of depression which currently lacks efficient treatment alternatives. However, the authors disagree about the underlying mechanism mediating these effects and doubt whether there is a sufficient degree of preclinical evidence to warrant the initiation of novel treatment approaches or widespread availability of the drug in clinical settings.

Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics

2014 | Abdallah, C. G., Duman, R. S., Krystal, J. H., Sanacora, G.

This review (2014) examines the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants.

The anterior cingulate cortex as a key locus of ketamine’s antidepressant action

2021 | Alexander, L., Jelen, L. A., Mehta, M. A., Young, A. H.

This review (2021) argues that the changes in the anterior cingulate cortex (AAC) are the key to ketamine's antidepressant effects. The subgenual and dorsal zones of the AAC are identified as most important in the ability to feel pleasure again.

Antidepressant actions of ketamine: from molecular mechanisms to clinical practice

2015 | Monteggia, L. M., Zarate, C. A.

This review (2015) provides an overview of the antidepressant mechanism of ketamine, clinical studies with ketamine, and its use in shaping the development of next-generation treatments, which include better tolerated non-ketamine NMDA antagonists and other non-NMDA glutamatergic modulators.

Ketamine safety and tolerability in clinical trials for treatment-resistant depression

2015 | Brallier, J., Chang, L. C., Charney, D. S., Foulkes, A., Iosifescu, D. V., Levitch, C. F., Mathew, S. J., Murrough, J. W., Perez, A. M., Wan, L.

This meta-analysis (2015) of open-label studies (n=97) examined the safety, tolerability, and acceptability of intravenous ketamine (35mg/70kg) infusion for patients with depression. They found that it was safe and well-tolerated with little to no psychotomimetic effects, adverse medical effects, or any increase in long-term substance abuse.

Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistance Depression and Major Depression with Suicide Ideation: A Meta-Analysis

2021 | Bahk, W., Kim, N., Lim, H., Na, H., Pae, C., Wang, S., Woo, Y.

This meta-analysis (s=7; n=1488) of double-blind placebo-controlled studies with those suffering from depression (MDD; TRD) and suicidal ideation (SI) found that esketamine (24-84mg) significantly improved scores on a measure of depression (MADRS) over the placebo up to 28 days alter, the SI scores were only significant within the first 24 hours.

Convergent Mechanisms Underlying Rapid Antidepressant Action

2018 | Duman, R. S., Gould, T. D., Thompson, S. M., Zanos, P., Zarate, C. A.

This review (2018) investigates the multiple mechanisms through which ketamine elicits its quick antidepressant effects.

Anti-inflammatory activity of ayahuasca and its implications for the treatment of neurological and psychiatric diseases

2021 | da Silva, M. G., Daros, G. C., de Bitencourt, R. M.

This review (2021) examines the antioxidant, anxiolytic (anxiety), and antidepressant effects of ayahuasca, with a particular emphasis on its anti-inflammatory action yielding therapeutic benefits for disorders related to neuroinflammatory factors.

Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development

2018 | Schenberg, E. E.

This theoretical commentary (2018) highlights the paradigm-shifting implications of psychedelic-assisted psychotherapy in light of a triple crisis within contemporary psychiatry, concerning the lack of reliable therapeutics, a heterogeneity of diagnoses, and a reductionist understanding of mental disorders that explains away the psyche by reducing it to underlying brain processes, whereas the new paradigm aims to incorporate these dimensions in a holistic understanding of human beings and the social factors of their culture and environment.

The psychedelic mystical experience in the human encounter with death

1971 | Pahnke, W. N.

This early review (1969) investigates the mystical experience and its relationship to death, with a focus on terminal cancer patients who had received psychedelics at that time. The correlation between the profoundness of the experience and therapeutic (long-term/non-acute) outcomes is also discussed.

Psilocybin in end of life care: Implications for further research

2021 | Summergrad, P.

This commentary (2016) examines the study design and the outcome measures of two randomized controlled studies that used psilocybin to treat mood and anxiety in patients undergoing palliative care. It can be concluded that the experiences of salience, meaningfulness, and healing that accompany the powerful spiritual experiences elicited by psilocybin, mediate the antidepressant and anxiolytic outcomes measures. Future investigations may investigate these phenomena in their own right, as well as replicate these findings in diverse clinical populations that aim to implement more robust blinding measures.

The fibrinolytic system: A new target for treatment of depression with psychedelics

2017 | Florova, G., Girard, R. B. S., Idell, R. D., Idell, S., Komissarov, A. A., Shetty, S.

This hypothesis-building article (2017) proposes that psychedelics such as psilocybin and ketamine exert antidepressant effects by restoring balance to the fibrinolytic system, a network of enzymes in the bloodstream that prevent blood clots from growing and reopen vessels closed by thrombosis. The authors postulate that psilocybin decreases coagulation promoting factors, neuroinflammation, and fibrin deposition in the brain, and restores the 5-HT2a receptor to pre-stress levels.

Administration of ketamine for unipolar and bipolar depression

2017 | Bartova, L., Carlberg, L., Gryglewski, G., Kasper, S., Kraus, C., Lanzenberger, R., Papageorgiou, K., Popovic, A., Rabl, U., Rybakowski, J. K., Spies, M., Vanicek, T., Willeit, M., Winkler, D.

This review (2017) examined clinical trials that investigated the antidepressant efficacy of ketamine for unipolar (MDD) and bipolar depression (BD). Results indicate that intravenous and intranasal ketamine produces strong reductions of depressive symptoms within a short period and with response rates up to 88%, however, depressive relapse occurs in up to 90% of patients within 2 weeks after treatment.

Psychedelic science in post-COVID-19 psychiatry

2020 | Alexander, L., Baker, A., Brennan, C., Burke, L., Crockett, M. T., Haran, M., Kelly, J. R., O’Keane, V.

This commentary (2020) examines how the COVID-19 pandemic has affected the trajectory of clinical trials investigating psilocybin-treatment for a wide range of conditions, some of which are likely to become even more prevalent in post-COVID-19 clinical psychiatry. Although many of these clinical trials have been temporarily stagnant due to safety measures, ongoing efforts from large scale clinical studies of psilocybin will provide valuable information on its safety, dose optimization, and its efficacy compared to a conventional selective serotonin reuptake inhibitor (SSRI) and additional studies will elucidate whether it is safe to combine them with psilocybin therapy.

Evaluating the Risk of Psilocybin for the Treatment of Bipolar Depression: A Review of the Research Literature and Published Case Studies

2021 | Adams, C., Bradley, E. R., DellaCrosse, M., Gallenstein, M. L., Gard, D. E., Garfinkle, E., Michalak, E. E., Penn, A., Pleet, M. M., Riley, L. S., Woolley, J. D.

This review (2021) finds that in the current literature there are some known, but limited, risks of activating mania with psilocybin for those with bipolar depression (BD). The review describes 17 cases of BD and the use of a range of psychedelics.

Oral ketamine for the treatment of pain and treatment-resistant depression

2016 | aan Het Rot, R., Balukova, S. M., Chaves, T. V., Kortekaas, R., Schoevers, R. A.

The meta-analysis (2016) examined the antidepressant effects of ketamine in specific regard to its oral administration route. In terms of safety, oral ketamine administration over longer time periods appears to be well-tolerated, but its long-term negative side-effects and the strength of its antidepressant efficacy remain understudied.

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

2016 | Albuquerque, E. X., Alkondon, M., Dossou, K. S. S., Elmer, G. I., Fang, Y., Fischell, J., Georgiou, P., Gould, T. D., Huang, X., Mayo, C. L., Moaddel, P. J., Morris, P. J., Pribut, H. J., Singh, N. S., Thomas, C. J., Thompson, S. M., Wainer, I. W., Yuan, P., Zanos, P., Zarate, C. A.

This review highlights findings from animal studies that examined whether a ketamine-metabolite (HNK) with fewer side effects is sufficient to induce antidepressant effects, as measured via behavioral, electroencephalographic, electrophysiological, and cellular measures which compared it to the effects of ketamine in mice. Results indicated that the metabolite can exert antidepressant effects through early activation of glutaminergic AMPA-receptors, independent of NMDA receptor inhibition that is typically induced by ketamine.

Clinical trials for rapid changes in suicidal ideation: Lessons from ketamine

2021 | Ballard, E. D., Farmer, C. A., Fields, J., Zarate, C. A.

This review (2021) examines methodological innovations within clinical trials investigating ketamine as a rapid-acting treatment option for depression or suicidal ideation (SI). The authors emphasize that the fast-acting dynamic of this treatment will enable the next generation of clinical trial designs to focus more on the development of better psychometric instruments, and more reliable biomarkers for assessing the efficacy of suicidal ideation treatment.

Indole Alkaloids from Plants as Potential Leads for Antidepressant Drugs: A Mini Review

2017 | Hamid, H. A., Ramli, A. N. M., Yusoff, M. M.

This review (2017) discusses bioactive compounds containing the indole moiety (half/part of a molecule) from plants that can potentially serve as antidepressive medication due to its relation to serotonin.

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

2015 | Ballard, E. D., Ladarola, N. D., Lundin, N. B., Machado-Vieira, R., Niciu, M. J., Nugent, A. C., Richards, E. M., Vande Voort, J. L., Zarate, C. A.

This review (2014) examines ketamine as a prospective treatment option for patients with depression and provides an overview of its role within the glutamate system, its antidepressant mechanisms of action, safety profile, and evidence from clinical studies that investigated the efficacy of single or multiple infusions. Furthermore, it compares alternative modes of ketamine administration and highlights fundamental research on other types of NMDA agonists that may have less psychotomimetic effects.

The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

2018 | Abdallah, C. G., Duman, R. S., Krystal, J. H., Sanacora, G.

This review (2018) examines the neurobiology of depression in light of the rapid fast-acting antidepressant properties of ketamine, with particular regard for the role of inhibitory and excitatory glutamate transmission. It is evident that the primary mechanism of ketamine is the induction of transient (minutes-to-hours) postsynaptic glutamate activation, which ultimately leads to a sustained (days-to-weeks) increase in synaptic formation and strength in the prefrontal cortex. However, it is unclear whether ketamine's effects on glutaminergic inhibition via extrasynaptic NMDA) receptors exert rapid or even slow antidepressant effects.

A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

2021 | Kwan, A. C., Savalia, N., Shao, L-X,

This opinion article (2021) postulates that ketamine and psychedelics substances enact their rapid fast-acting antidepressant effects by means of promoting neuroplasticity in a heterogeneous manner, by enhancing or suppressing dendritic excitability across different parts of the cellular membrane. Although precise measurements of this pharmacological effect across the entire dendritic tree are currently still lacking, the authors hypothesize that the spatial mismatches in the opposing effects of these drugs drive neuroplasticity at specific dendritic hotspots, depending on the microcircuitry of their respective target neurons.

Targeting glutamate signalling in depression: progress and prospects

2021 | Abdallah, C. G., Mathew, S. J., Murrough, J. W.

This review (2017) examines the history, rationale, and efficacy of glutamate-modulating agents in treating depression. Ketamine has emerged as the prototypical fast-acting antidepressant and has yielded compelling hypotheses about the role of glutamate, although the role of its effects on NMDA receptor inhibition still remains unclear as to whether it alleviates depression. Preliminary evidence also suggests that ketamine-like drugs exert antidepressant properties by regulating monoamine signaling, opioid signaling, inflammatory systems, or even epigenetic mechanisms.

Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine

2016 | Ballard, E. D., Lener, M. S., Niciu, M. J., Nugent, A. C., Park, L. T., Park, M., Zarate, C. A.

This review (2017) examines ketamine's rapid antidepressant efficacy with respect to evidence that it can neurochemical/physiological disturbances, such as abnormalities in excitatory and/or inhibitory neurotransmission in association with altered brain levels of glutamate and gamma-aminobutyric acid. It highlights neuroimaging studies to support the notion that glutamatergic modulation may be a viable biomarker for investigating depression in future studies.

The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature

2019 | Frankenthaler, M., Goldman, N., Klepacz, L.

This comprehensive review (2019) compared the efficacy of ketamine treatment for pain and depression within palliative care across administration route and dosing regimen. Efficacy of pain treatment exhibited generally inconclusive and mixed results, but studies that administered ketamine either epidurally or intrathecally demonstrated significant analgesia, in contrast, to subcutaneously or intravenous administration routes. Depression was improved across all relevant studies and was sustained the longest during a daily dosing regimen, whereas a single or a multidose did not exert effects beyond 7 days after administration.

Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review

2016 | Dale, E., du Jardin, K. G., Elfving, B., Müller, H. K., Sanchez, C., Wegener, G.

This review (2016) examines a number of preclinical reports which suggest that serotonergic neurotransmission could play an important role in ketamine's antidepressant-like activity. The authors hypothesize that ketamine may alleviate depression by increasing serotonin levels in the prefrontal cortex NMDA receptor inhibition and activation of AMPA glutamate receptors. Preclinical animal studies indicate that ketamine may also have an affinity towards serotonergic receptors, including the 5-HT2A receptor, in addition to glutamatergic neurotransmission.

Efficacy and safety of ketamine in bipolar depression: A systematic review

2017 | Alberich, S., González-Pinto, A., López, P., Martínez-Cengotitabengoa, M., Nuñez, N. A., Vieta, E., Zorrilla, I.

This review (2017) compared the safety and efficacy of ketamine for bipolar depression across scientific studies (1 clinical trial, 4 case studies, 5 cohort studies), which showed that symptoms are reduced swiftly and effectively in response to treatment, but they reappear relatively quickly within 3-14 days depending on the scale used to measure symptoms. Ketamine may be considered safe and effective for treating some cases of bipolar depression, although it has a short duration of action, in the absence of confirming studies designed specifically for bipolar depression.

Is ketamine an appropriate alternative to ECT for patients with treatment resistant depression? A systematic review

2020 | Kamphuis, J., Schoevers, R. A., Smith-Apeldoorn, S. Y., Spaans, H., Veraart, J. K. E.

This review (2020; 6 studies) compares ketamine with ECT as treatments for treatment-resistant depression (TRD). The authors preliminarily conclude that ketamine may show effects faster, but these effects seem to be less durable.

Treating Addiction: Perspectives from EEG and Imaging Studies on Psychedelics

2016 | de Araujo, D. B., Tófoli, L.F.

This book chapter (2016) reviews the evidence regarding the effects of psychedelics on the brain and their potential as treatments for psychiatric and addictive disorders.

Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: a systematic review

2021 | Benyamina, A., Hermand, M., Karila, L., Pétillion, A., Romeo, B.

This systematic review (2021) of studies from 1990 to 2020 aimed to determine factors that can predict successful response to psychedelic treatment. In a variety of disorders, the authors found that the intensity of the experience was the best such predictor.

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

2019 | Hashimoto, K.

This historic review (2019) examines cellular mechanisms underlying the antidepressant effects of the R(-) and S(+) ketamine enantiomers and their norketamine and hydroxynorketamine metabolites. Although S(+) ketamine exhibits greater affinity to the NMDAR, which is believed to be the mediator of its antidepressant effect, preclinical evidence from animal models suggests that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects with less detrimental side‐effects. Given that the phase I clinical studies on R(-)ketamine and hydroxynorketamine are now underway, future studies will be able to perform a direct comparison of their efficacy to treat patients with depression.

Nonanesthetic Effects of Ketamine: A Review Article

2018 | Blaise, G., Eldufani, J., Nekoui, A.

This review (2018) examines (preliminary) evidence of the medical benefits of the non-anesthetic effects of ketamine, as well as supporting evidence of the effectiveness and tolerability of ketamine for improving pain conditions, depression, memory function in Alzheimer's disease, and brain damage after stroke. It also examines underlying mechanisms that exert these effects by stimulating or blocking certain neuroreceptor pathways.

Mechanisms of ketamine action as an antidepressant

2018 | Gould, T. D., Zanos, P.

This review (2018) examines the neurobiological mechanisms underlying the antidepressant effects of ketamine. Whereas previous presumed that NMDA receptor inhibition is the principal mechanism, new evidence suggests that additional receptor-pathways that are specific to its downstream metabolite hydroxynorketamine are sufficient to improve depression (in animal studies) without blocking NMDA.

Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

2020 | Alitalo, O., Kohtala, S., Rantamäki, T., Rosenholm, M., Rozov, S.

This theory-building paper (2020) proposes that the circadian rhythm may be an important factor in the antidepressant effect of ketamine therapies.

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation

2021 | Berk, M., Brietzke, E., Dodd ,S., Gorwood, P., Ho, R., Iosifescu, D. V., Jaramillo, C. L., Kasper, S., Kratiuk, K., Lee, J. G., Lee, Y., Lui, L. M. W., Mansur, R. B., McIntyre, R. S., Murrough, J. W., Nemeroff, C. B., Papakostas, G. I., Rosenblat, J. D., Sanacora, G., Stahl, S., Subramaniapillai, M., Thase, M., Vieta, E., Young, A. H., Zarate, C. A.

This study (2021), written by a large group of international experts, reviews the state of knowledge around ketamine and esketamine as potential treatments for treatment-resistant depression (TRD). Special attention is given to the risk of suicide after discontinuing (es)ketamine treatment.

Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

2021 | Baker, G., Dos Santos, R. G., Dursun, S., Hallak, J. E.

This review (2021) summarizes the available evidence regarding the potential of LSD, psilocybin, and ayahuasca as rapidly effective antidepressant therapies. Results are promising but still limited.

Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature

2018 | Cusin, C., Deckersbach, T., Felicione, J. M., Gosai, A., Ionescu, D. F., Shapero, B. G., Shin, P.

This review (2018) examines the neural correlates of ketamine-associated brain changes in patients with depression. Although ketamine affects different areas of the brain in various ways, its most notable effects were found in the subgenual anterior cingulate cortex, posterior cingulate cortex, prefrontal cortex, and hippocampus. Ketamine affects emotional blunting, which may be associated with reduced limbic responses to emotional stimuli, and increase neural activity in reward processing. It also reduces brain activation in regions, such as the Default Mode Network (DMN), associated with self-monitoring, which may be linked to its dissociative effects.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

2014 | Barnes, G., Baumeister, D., Giaroli, G., Tracy, D.

This review (2014) examines the effects of psychedelic drugs with regard to their pharmacodynamics and molecular biology, their electrophysiological and neuroimaging profile, and summarizes the evidence for potential therapeutic mechanisms of action, including effects on neurogenesis, cortical networks, and the immune system. It also examines the clinical profile of psychedelic substances with regard to risks for healthy individuals, as well as the potential to treat clinical conditions such as depression, notwithstanding the criminalized status of psychedelics, despite negligible risk and a lack of evidence for its alleged adverse effects.

Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy

2013 | Caddy, C., Giaroli, G., Shergill, S. S., Tracy, D., White, T. P.

This systematic review and meta-analysis (2013, n=629) analyzed data from all trials investigating the antidepressant efficacy of ketamine up to publication date, and provides a systematic overview of its neurobiological and pharmacodynamic profile. The vast majority of the studies showed that ketamine infusion rapid antidepressant response, and an independent rapid antisuicidal effect.

Ketamine as a promising prototype for a new generation of rapid-acting antidepressants

2015 | Abdallah, C. G., Averill, L. A., Krystal, J. H.

This review (2015) summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action that may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets, and directions for future research.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

2014 | Brutsche, N. E., Guevara, S., Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J., Nolan, N. M., Richards, E. M., Zarate, C. A.

This meta-analysis (n=108) examined whether the rapid antidepressant effect of a single subanesthetic ketamine (35mg/70kg) infusion is mediated by its dissociative side-effects or other symptoms related to its psychotomimetic profile. The analysis revealed that its dissociative effect was the only mediator that predicted a robust and sustained antidepressant efficacy.

Ketamine Users Have High Rates of Psychosis and/or Depression

2015 | Chan, F., Liang, H. J., Tang, K. L., Tang, W. K., Ungvari, G. S.

This meta-analysis (n=129) evaluated the relation between long-term treatment with ketamine and the frequency of psychotic and mood disorders, amongst patients located in Hong Kong, China. According to standardized diagnostic criteria, psychosis and/or depression were very common amongst these patients, which raises the issue of safety when considering ketamine for long-term treatment of depression.

The use of ketamine as an antidepressant: a systematic review and meta-analysis

2015 | Coyle, C. M., Laws, K. R.

This meta-analysis (2015; n=437) examined the antidepressant effects of ketamine, with regard to its efficacy over short and long-term periods, across single or repeated infusions, moderating variables related to the experimental design, and efficacy amongst patients with depression (MDD) or bipolar disorder (BD). Results conveyed that ketamine is an effective and rapid treatment for depression in the short term, with large antidepressant effects emerging after 4 hours and lasting up to 2 weeks post-infusion in participants with a primary diagnosis of MDD or BD. Repeated infusion showed larger effect sizes but did not extend the duration of antidepressant effect.

Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression

2015 | Andrade, C.

This article (2015) examines the advantages and applications of intranasal drug delivery, with a particular focus on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression. The article contrasts intranasal delivery to oral and sublingual delivery methods, which are less effective with regards to their bioavailability, crossing of the blood-brain-barrier, and rapid onset of drug effects.

Integrating psychotherapy and psychopharmacology: psychedelic-assisted psychotherapy and other combined treatments

2020 | Feduccia, A. A., Garel, N., Greenway, K. T., Jerome, L.

This meta-review (2020) examines the therapeutic frameworks surrounding contemporary practices of psychedelic-assisted psychotherapy, with regard to the historic development of therapeutic models and contemporary insights into extra-pharmacological factors and underlying mechanisms. They highlight that these therapies entail greater environmental sensitivity from the patient's perspective, which requires more meticulous attention for the preparation of the set and setting, a considerably resource-intensive endeavor.

Ketamine for treatment-resistant depression: recent developments and clinical applications

2016 | Iosifescu, D. V., Murrough, J. W., Schwartz, J.

This clinical review (2016) examines the fasting-acting effects of ketamine for alleviating symptoms of major depressive disorder (MDD), with regard to its administration method, its safety profile, and its general effects on suicidal ideation, anhedonia, cognition. It also examines which patient profiles predict the most effective response duration while highlighting that the manifestation of depressive symptoms make it challenging to predict the efficacy of ketamine, and although further research is underway to elucidate the role of genetic, central neurobiological, and peripheral measures, it is still too early to recommend their adoption in clinical practice.

Ketamine for Treatment-Resistant Unipolar and Bipolar Major Depression: Critical Review and Implications for Clinical Practice

2016 | Bobo, W. V., Croarkin, P. E., Frye, M. A., Leung, J. G., Tye, S. J., Vande Voort, J. L.

This review (2016) examines the clinical efficacy of ketamine as fast-acting pharmacotherapy for major depressive disorder and bipolar disorder (BP), in light of the available evidence. In the authors' view, there is insufficient empirical support for the early adoption of ketamine into routine practice, given the lack of data on the longer-term safety of ketamine as an antidepressant therapy, which will require the development of clinical protocols with standardized screening, clinical phenotyping, and follow-up procedures.

Ketamine: A Paradigm Shift for Depression Research and Treatment

2019 | Abdallah, C. G., Charney, D. S., Duman, R. S., Krystal, J. H., Sanacora, G.

This review and perspective paper (2019) gives a high-level overview of what we know about ketamine's effects and how it has changed our perspective on (the treatment of) depression.

Ketamine: A tale of two enantiomers

2020 | Jelen, L. A., Stone, J. M., Young, A. H.

This review (2020) summarizes the clinical findings of ketamine as a treatment for depression, and discusses the differences between (S)-ketamine and (R)-ketamine.

From Hofmann to the Haight Ashbury, and into the Future: The Past and Potential of Lysergic Acid Diethlyamide

2014 | Dickerson Davidson, L., Raswyck, G. E., Smith, D. E.

This review (2014) summarises the history of LSD research and outlines the potential applications in the future.

Psilocybin-assisted therapy of major depressive disorder using Acceptance and Commitment Therapy as a therapeutic frame

2020 | Guss, J., Krause, R., Reed, S., Skinta, M. D., Sloshower, J. A., Wallace, R. M., Williams, M. T.

This theory-building paper (2020) argues for the synergy between Acceptance and Commitment Therapy (ACT) and psilocybin-assisted therapy, describes the process, and limitations to using this framework.

Potential Therapeutic Effects of Psilocybin

2017 | Griffiths, R. R., Johnson, M. W.

This review (2017) evaluates the therapeutic research into psilocybin as a treatment for addiction, treatment-resistant depression, and mood and anxiety disorders. The authors also analyse the safety data from these clinical trials.

Psychedelics and Psychedelic-Assisted Psychotherapy

2020 | Carpenter, L. L., Kalin, N. H., McDonald, W., Nemeroff, C. B., Reiff, C. M., Richman, E. E., Rodriguez, C. I., Widge, A. S.

This review (2020) finds that randomized clinical trials (RCTs) support the efficacy of various psychedelic-assisted therapies for mental health disorders.

An Update on the Efficacy and Tolerability of Oral Ketamine for Major Depression: A Systematic Review and Meta-Analysis

2020 | Frye, M. A., Joseph, B., Kung, S., Nuñez, N. A., Pahwa, M., Prokop, L. J., Schak, K. M., Seshadri, A., Singh, B., Voort, J. L. V.

This meta-analysis (n=161) of 10 studies (3 RCTs) found a marginal efficacy of oral ketamine for major depressive disorder (MDD).

Classical Psychedelics as Therapeutics in Psychiatry - Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders

2021 | Mertens, L. J., Preller, K. H.

This review (2021) investigates the studies with psychedelics (psilocybin, LSD, ayahuasca) since 2011 for substance use disorders (SUD) and mood disorders (e.g. depression). More (rigorous) studies (RCTs) are needed.

Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK

2008 | Green, A. R.

This review (2008) retraces the 20-year scientific history of serotonin (5-HT) research in the UK.

Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies

2016 | Chen, J., Han, Y., Li, P., Li, Q., Liu, Y., Wang, H., Xie, P, Zhang, Y., Zheng, P., Zhou, X., Zou, D.

This meta-analysis (2016, 9 RCT studies, n=368) suggests that ketamine is an effective short-term treatment for major depressive disorder (MDD).

Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis

2020 | Bahji, A., Vazquez, G. H., Zarate, C. A.

This systemic review and meta-analysis (2020) of 24 clinical trials (n=1877) assessed the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression. The authors found that intravenous ketamine appeared to be more efficacious than intranasal esketamine for the treatment of depression.

Management of treatment-resistant depression: Challenges and strategies

2020 | Blumberger, D. M., Daskalakis, Z. J., Voineskos, D.

This review (2020) details the background and therapeutic challenges associated with treatment-resistant depression. A wide range of treatments are evaluated, including novel therapeutics such as ketamine and psilocybin.

A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses

2020 | Chi, T., Gold, J. A.

This review (2020) presents modern human studies into psychedelic drugs, including psilocybin, LSD, MDMA, and ayahuasca in the treatment of various psychiatric illnesses, including treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. Safety and efficacy data are also presented, from both human and animal studies.

The Emerging Role of Psilocybin and MDMA in the Treatment of Mental Illness

2020 | Cha, D. S., Chen-Li, D., El-Halabi, S., Gill, B., Gill, H., Ho, R., Lee, Y., Lipsitz, O., Majeed, A., Mansur, R. B., McIntyre, R. S., Nasri, F., Rodrigues, N. B., Rosenblat, J. D.

This narrative review (2020) evaluates the therapeutic potential of psilocybin and MDMA for the treatment of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and anxiety. The review explains the need for effective mental health treatments and highlights the lack of dose-response studies in placebo-controlled settings with a real-world clinical population.

Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants

2021 | de Manicor, M., Galvão-Coelho, N. L., Gonzales, M., Marx, W., Perkins, D., Sarris, J., Sinclair, J.

This meta-analytic review (2021, n=257) found that psychedelics provide improvements in mood for patients with mood disorders (and healthy subjects), both short (3h to 1d) and long-term (up to 60d).

The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: a systematic review

2020 | Kosten, T. R., Mathai, D. S., Meyer, M. J., Storch, E. A.

This paper (2020) aimed to review the relationship between ketamine's anti-depressant effect and its subjective effects and found that they were correlated in some studies (1/3 studies).

Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories

2016 | Bauer, M., Chawla, J. M., Correll, C. U., Hagi, K., Kane, J. M., Kishimoto, T., Zarate, C. A.

This meta-analysis (2016; 14 RCTs) found that single infusions of ketamine (to a lesser extent, non-ketamine NMDAR antagonists) has rapid anti-depressant effects that can last for up to one week.

A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis

2020 | Duffy, J. M. N., Illingworth, B. J. G., Jelen, L. A., Lambarth, A. T., Lewis, D. J., Rucker, J.

This systematic review and meta-analysis (2020) of MDMA-assisted therapy for PTSD, found that over four RCT's (n=67), PTSD scores (CAPS-IV) were lower in the 75mg and 125mg groups (not 100mg), and depression scores (BDI) only in the 75mg group.

Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review

2018 | Gasser, P., Gutwinski, S., Hermle, L., Jungaberle, H., Majic, T., Reiche, S.

This systematic review (2018) of 11 clinical trials (n=445) found that psychedelics (LSD, psilocybin) reduced symptoms of depression and anxiety in patients with life-threatening diseases (end-of-life).

Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies

2020 | Andersen, K. A. A., Carhart-Harris, R. L., Erritzoe, D., Nutt, D. J.

This systematic review (2020) looked at 10 modern studies (n=188) on psychedelics (psilocybin, ayahuasca, LSD) for the treatment of a variety of mental health disorders. The review found the studies to provide evidence for efficacy (up to months later) and safety.

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years

2016 | Crippa, J. A., Dos Santos, R. G., Hallak, J. E., Osório, F. L., Riba, J., Zuardi, A. W.

This systematic review (2015) identified (only) 6 (very high) quality studies and argues that these psychedelics may be useful tools for the treatment of mental health disorders.

Psychedelics in the treatment of unipolar mood disorders: a systematic review

2016 | Flynn, S., Frowde, K. D., Jelen, L. A., Rucker, J., Young, A. H.

This meta-analysis (n=423) of studies before prohibition (1949-73) of treating unipolar mood disorders (depression) showed that, besides the many flaws of the studies, the results were positive (79% of participants showed improvements, few side-effects).

Classical hallucinogens and neuroimaging: A systematic review of human studies: hallucinogens and neuroimaging

2016 | Crippa, J. A., Dos Santos, R. G., Hallak, J. E., Osório, F. L.

A systematic review (2016) found that psychedelics (serotonergic 'hallucinogens') have a distinct influence on brain structures that have anxiolytic (anxiety-relieving), antidepressant, and antiaddictive properties.

The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis

2020 | Goldberg, S. B., Hutson, P. R., Nicholas, C. R., Pace, B. T., Raison, C. L.

This meta-analysis (2020) reported favorably on four trials (n=117) that studied the effect of psilocybin-assisted therapy for anxiety and depression.

A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

2020 | Bathje, G. J., Chwyl, C., Davis, A. K., Lancelotta, R., Luoma, J. B.

This meta-analysis of nine placebo-controlled trials (n=211) showed a very large effect size (g=1.21) of treatment on four mental health conditions (PTSD, end-of-life anxiety, depression, social anxiety among autistic adults).

Relationships between reduction in symptoms and restoration of function and wellbeing: Outcomes of the Oral Ketamine Trial on Suicidality (OKTOS)

2021| Beaudequin, D. A., Can, A. T., Dutton, M., Forsyth, C. G., Hermens, D. F., Jensen, E., Jones, M., Lagopoulos, J., Scherman, J., Schwenn, P. E., Yang, C.

In this open-label study (n=30) participants received six oral sub-anaesthetic doses of ketamine, one dose a week over six weeks. The initial dose was 35mg/70kg which increased to a max of 210mg/70kg by week six. Although restoration of function and wellbeing did improve, these effect sizes were smaller than for suicidality and depression outcomes suggesting that reduction in these outcomes may not be necessary for full restoration of function and wellbeing.

Psychedelic mushrooms in the USA: Knowledge, patterns of use and association with health outcomes

2021| Lerer, B., Lerer, L. B., Matzopoulos, R., Morlock, A., Morlock, R.

This preprint survey study (n=7139) assessed the use of psychedelic mushrooms amongst adults in the US. The survey found that people generally self medicate with psychedelic mushrooms for reasons related to mental health, with users reporting significantly higher levels of anxiety and depression. The study concludes with a call for a use-related harm reduction strategy for psychedelic mushrooms in the US.

Persisting effects of ayahuasca on empathy, creative thinking, decentering, personality, and well-being

2021| Kiraga, M. K., Kuypers, K. P. C., Mason, N. L., Ramaekers, J. G., Toennes, S. W., Uthaug, M. V., van Oorsouw, K.

This provisionally accepted study (n=40) explored the effects of ayahuasca on processes involved in stress-related psychopathologies. Volunteers attending an ayahuasca ceremony were given a series of questionnaires at baseline, the morning after and one week after the experience. Researchers found ingesting ayahuasca is associated with positive therapeutic outcomes.

Sub-acute and long-term effects of ayahuasca on mental health and well-being in healthy ceremony attendants: A replication study

2021| Broers, N. J., Mason, N. L., Ramaekers, J. G., Uthaug, M. V., van Oorsouw, K.

This observational study (n=73) replicated an earlier ayahuasca ceremony study, but this time found only improvements in self-reported stress four weeks later, no reduction in depression was observed. The study did also replicate findings of increased life satisfaction the day after the ceremony, which returned to baseline four weeks after.

A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats

2020| Carrera, C. S. I., Fabius, S., Havel, V., Prieto, J. P., Reyes, A. L., Rodríguez, P., Sames, D., Urbanavicius, J.

This rodent study investigates behavioral effects of acute ibogaine and noribogaine administration in rats. It found that both produced a dose-and time-dependent antidepressant effect without substantial changes in animal locomotor activity.

Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant

2015| Ameli, R., Ballard, E. D., Brutsche, N. E., Luckenbaugh, D. A., Niciu, M. J., Richards E. M., Vande Voort, J. L., Walls, T. S., Zarate, C. A.

This study (n=60) of randomized, placebo-controlled, crossover clinical trials appraises suicidal ideation (SI) with ketamine infusion in persons with treatment-resistant depression (TRD). The results indicated improvement in suicidal thoughts after ketamine infusion and the measures are sensitive to these changes.

Psychedelics not linked to mental health problems or suicidal behavior: A population study

2015| Johansen, P. Ø., Krebs, T. S.

This 2015 observational survey study (n=135 095) investigated the association between lifetime psychedelic use (LSD, psilocybin, mescaline) and mental health problems, but found no indication of increased likelihood for psychological distress, mental health treatment, suicidal behavior, depression, or anxiety amongst psychedelic users (n=19 299). These results contest the justification for prohibiting psychedelics as a public health measure.

Rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review

2017| Araújo-de-Freitas, L., Argolo, F. C., Correia-Melo, F. S., Kapczinski, F., Lacerda, A. L. T., Leal, G. C., Quarantini, L. C.

This retrospective chart review (n=27) investigates the efficacy and safety of rapid infusion of esketamine in patients with treatment-resistant depression (TRD) and bipolar depression (BD). The study found that rapid infusion of esketamine is not the best choice for treatment-resistant depression due to tolerability issues. Additionally, patients reported dissociative symptoms ranging from mild to severe and found them to be disturbing.

Prophylactic Ketamine Attenuates Learned Fear

2017| Brachman, R. A., Denny, C. A., LaGamma, C. T., Lim, S. C., McGowan, J. C., Neria, Y., Tsitsiklis, M.

This saline-controlled rodent study evaluates whether ketamine (30 mg/kg) is effective in reducing fear or preventing fear reactivation using a contextual fear conditioning (CFC) paradigm. The study found ketamine as most useful in the clinic if administered in a prophylactic manner a week prior to a stressor to protect against increased fear responses to aversive stimuli.

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies

2021| Daly, E. J., Lin, X., Macaluso, M., Nash, A. I., Nelson, J. C., Salvadore, G., Singh, J. B., Turkoz, I., Tymofyeyev, Y., Wilkinson, S. T., Williamson, D.

This pooled analysis of two phase III studies (n=518, TRANSFORM) finds that for those who didn’t respond, continued treatment may still be beneficial. This was both true for the esketamine group and the group that received a placebo.

The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder

2021| Borentain, S., Daly, E. J., Fedgchin, M., Ionescu, D. F., Salvadore, G., Singh, J. B., Starr, H. L., Thase, M., Trivedi, M. H., Turkoz, I.

This post-approval, double-blind, placebo-controlled study (n=223, TRANSFORM-2) finds that those with comorbid anxiety (72%) responded just as well as those without anxiety to esketamine (56-84mg, 4 weeks, combined with SSRI) treatment.

Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome

2017| Charney, D. S., Costi, S., Horn, S. R., Iosifescu, D. V., Kiraly, D. D., Murrough, J. W., Schwartz, J., Van Dam, N. T.

This between-subjects study (n=59) examined the peripheral immune profiles in patients with depression (n=33) before and after ketamine treatment (35mg/70kg) compared to healthy participants (n=26). Pro-inflammatory cytokines were consistently elevated among patients with depression, and although ketamine infusion transiently lowers these markers of inflammation, these changes appear not to be directly linked to clinical antidepressant effects on the long-term.

Working with Weirdness: A Response to “Moving Past Mysticism in Psychedelic Science”

2021| Breeksema, J. J., van Elk, M.

In this opposing viewpoint to 'Moving Past Mysticism', an article which argued that 'mystical' constructs are overly laden with beliefs and do not suffice objective measurement, it is argued that 'mystical experiences' have a rich history of scientific investigation as the authors lay out a brief summary of their underlying constructs and empiric validation. They argue that the sole reliance on brain-based explanations is essentially a type of 'neuroenchantment' that ignores the transformative impact of subjective experiences on people’s lives, behavior, and values. The authors state that research should remain open to all varieties of the psychedelic experience, including weird and extraordinary states that do not conform to western culture and its expectations.

Mental health of a self-selected sample of psychedelic users and self-medication practices with psychedelics

2018| Kuypers, K. P. C., Mason, N. L.

The observational survey study (n=1,967) investigated the frequency and efficacy of self-medication practices amongst psychedelic users and found that the prevalence of lifetime psychopathologies amongst psychedelic users was higher than in the general population. Although psychedelics were seldom used for self-medication, those who did use psychedelics in this manner reported it to be more effective than the current lines of treatment for mental illness.

Four weekly ayahuasca sessions lead to increases in “acceptance” capacities: a comparison study with a standard 8-week mindfulness training program

2018| Domínguez-Clavé, E., Elices, M., Feilding, A., García-Campayo, J., Navarro-Gil, M., Pascual, J. C., Riba, J., Soler, J.

This observational cohort study (n=20) compared the effects of four consecutive ayahuasca sessions with those of standard mindfulness training between two independent groups of healthy individuals. Although mindfulness training had an overall greater impact on mindfulness capacities, ayahuasca intake led to spontaneous increases in certain aspects of acceptance towards potentially distressing emotions and thoughts.

The Impact of Ayahuasca on Suicidality: Results From a Randomized Controlled Trial

2019| Araújo, D. B., Arcoverde, E., Hallak, J. E., Maia-de-Oliveira, J. P., Palhano-Fontes, F., Zeifman, R. J.

This analysis of a double-blind, parallel-arm, randomized placebo-controlled trial (n=29) investigates the impact of ayahuasca on suicidality (SI) in individuals with treatment-resistant depression (TRD). It found that ayahuasca may show potential as a fast-acting and innovative intervention for SI but didn't find significant results (only a trend with a large effect size). This is the first study to investigate ayahuasca for SI.

Real-world effectiveness of repeated ketamine infusions for treatment resistant depression during the COVID-19 pandemic

2021| Di Vincenzo, J. D., Kratiuk, K., Lee, Y., Lipsitz, O., McIntyre, R. S., Rodrigues, N. B., Rosenblat, J. D., Subramaniapillai, M.

This open-label study (n=267) investigated if Covid had any impact on the effectiveness of ketamine treatments (iv, 4x 35-53mg/70kg) for depression (TRD). Patients in both groups experience significant and comparable improvements in depressive symptoms, suicidal ideation (SI), and anxiety.

Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open-Label Study

2018| Albott, C. S., Amatya, P., Carstedt, P., Cullen, K. R., Eberly, L. E., Gunlicks-Stoessel, M., Horek, N., Klimes-Dougan, B., Lim, K. O., Reigstad, K., Ren, Y., Roback, M . G., Samikoglu, A., Schreiner, M. W., Tye, S.

This open-label study (n=13) probed into the efficacy and tolerability of intravenous ketamine in adolescents with treatment-resistant depression (TRD), and investigated clinical response predictors using the Children's Depression Rating Scale-Revised (CDRS-R) and the Clinician-Administered Dissociative States Scale (CADSS). It supported the potential of ketamine in the treatment of adolescent patients with TRD and a dose-response relationship but called for larger sample size and overcoming limitations such as the open-label design and further research.

Ketamine and Attentional Bias Toward Emotional Faces: Dynamic Causal Modeling of Magnetoencephalographic Connectivity in Treatment-Resistant Depression

2021| Galiano, C. S., Gilbert, J. R., Nugent, A. C., Zarate, C. A.

This double-blind, placebo-controlled, within-subjects study (n=34) used magnetoencephalographic (MEG) recordings to find a correlation between anti-depression effects (for those suffering from depression; TRD & BD) and neurological changes (e.g. faster GABA, AMPA, and NMDA transmission in specific brain areas).

Harmine produces antidepressant-like effects via restoration of astrocytic functions

2017| Chen, X., Gong, Y., Huang, C., Ling, Y., Liu, F., Tong, L., Wang, P., Wu, J., Zhu, L.

This rodent study explores the effects of harmine treatment on chronic unpredictable stress (CUS)-induced depressive-like behaviors and astrocytic dysfunctions. The results demonstrated that the development of depression is critically contributed by astrocytic dysfunction as a potential mechanism and harmine induces antidepressant-like effects likely via restoration of the said astrocytic functions.

Case Report: Ketamine for Pain and Depression in Advanced Cancer

2018| Atayee, R., Bruner, H. C., Sexton, J. D.

This case report explores the potential of ketamine (35mg/70kg) for pain and depression in advanced cancer. It demonstrated how a patient suffering from neuropathic pain from advanced cancer and severe depression showed a dramatic decrease in pain and resolution of severe depression symptoms post an intravenous infusion of ketamine.

Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II)

2021| Canuso, C. M., Drevets, W. C., Fu, D. J., Hough, D., Ionescu, D. F., Kasper, S., Lane, R., Lim, P., Manji, H., Qiu, X.

This double-blind, placebo-controlled, randomized study (n=230) evaluated esketamine nasal spray (84 mg) for rapid reduction of depressive symptoms in patients with major depressive disorder (MDD) who have active suicide ideation with intent. It found that patients in both treatment categories demonstrated a very significant decrease in depressive symptoms over placebo and confirmed that esketamine nasal spray could play a role in helping critically ill patients with MDD who have suicidal intent.

Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression

2018| Bai, Y. M., Chen, M. H., Cheng, C. M., Gueorguieva, R., Hong, C. J., Krystal, J. H., Li, C. T., Lin, W. C., Su, T. P., Tu, P. C.

This double-blind, randomized, parallel-group, placebo-controlled trial study (n=71) examines adjunctive ketamine's dose-related effects in Taiwanese patients with treatment-resistant depression (TRD). This first such report showing the dose-related efficacy of ketamine for TRD, and characterized ketamine effects in a genotyped Chinese group in which 83% of patients had at least one copy of the BDNF gene's lower functioning Met allele.

Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications

2017| Abagyan, R., Atayee, R., Cohen, I. V., Makunts, T.

The study evaluates population-scale data for clarity on the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications. It shows that patients with ketamine demonstrated a significantly lower frequency of reports of depression, pain, and opioid-induced side effects, as compared to patients who used other combinations of drugs for pain. The conclusion supported ketamine's potential in pain management pharmacotherapy.

Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders

2017| Anderson-Fahey, B., Glue, P., Gray, A., Harland, S., Le Nedelec, M., McNaughton, N., Medlicott, N. J., Neehoff, S.

This ascending single-dose study (n=12) evaluates the dose-related effects of ketamine (18-70mg/70kg) on patients with anxiety symptoms with treatment-resistant anxiety disorders. Ten of the twelve participants (83%) found relief for up to seven days. The results support ketamine as a potential therapeutic alternative for patients with anxiety disorders.

Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial

2017| Burke, A. K., Cooper, T. B., Ellis, S. P., Grunebaum, M. F., Keilp, J. G., Mann, J. J., Marver, J. E., Milak, M. S., Moitra, V. K., Oquendo, M. A., Sublette, M. E.

This midazolam-controlled randomized clinical trial study (n=16) compares ketamine and midazolam (another anesthetic) to investigate their feasibility and effect on suicidal ideation (SI) in bipolar depression (BD) using the Scale for Suicidal Ideation (SSI) score. The results substantiate feasibility with improvement in memory and BDNF as promising biomarkers and that ketamine effects showing more reduction in suicidal thoughts than with midazolam, although it was not statistically significant; this was possibly due to a small sample so a full-scale trial is needed.

Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism

2019| Bentzley, B. S., Blasey, C., Hawkins, J., Heifets, B. D., Lyons, D. M., Schatzberg, A. F., Sudheimer, K. D., Williams, N. R.

This double-blind placebo-controlled clinical trial (n=12) examined the effects of naltrexone and ketamine on suicidal ideation (SI) and found that naltrexone attenuates (blocks) the effects of ketamine. It's proposed, just as with the antidepressant effect of ketamine, that it requires opioid receptor activation.

Repeated ketamine injections in synergy with antidepressants for treating refractory depression: A case showing 6-month improvement

2019| Li, Z., Su, B., Wang, L., Wang, M., Xiong, Z., Yang, Y.

This case study (2019) explores repeated intravenous (IV) ketamine in synergy with antidepressants to treat refractory depression (TRD). It found that high-dose IV ketamine may stably enhance depressive symptoms and cognitive function in patients with TRD who do not tend to respond to a rapid intravenous dose of standard-dose ketamine.

Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial

2021| Elder, C., Fasula, M., Fenton, L., Joormann, J., Kitay, B., Ortiz Lopez, M., Rhee, T. G., Sanacora, G., Webler, R., Wilkinson, S. T.

This randomized study (n=28) with patient who responded to ketamine treatment for depression (TRD) received either cognitive-behavioral therapy (CBT) or conventional treatment. There was a significant (moderate effect) on a score of depression (QIDS) that favored the CBT group at the end of the study (14 weeks).

R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects

2020| Hashimoto, K., Ma, M., Ren, Q., Shirayama, Y., Yang, C., Yao, M., Zhang, J-C.

This mice study proposed that, unlike S-ketamine, R-ketamine can induce a sustained antidepressant effect, mediated by higher BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. The authors also noted that R-ketamine is more potent, long-lasting and safe antidepressant than S-ketamine considering that R-ketamine seems to be free of "psychotomimetic side effects" and abuse potential.

Combination therapy with transcranial magnetic stimulation and ketamine for treatment-resistant depression: A long-term retrospective review of clinical use

2019| Best, S. R. D., Haustrup, N., Pavel, D. G.

This long-term follow-up (n=28) found that transcranial magnetic stimulation (TMS) combined with ketamine infusions, for those suffering from depression (TRD) was effective up to two years later. The administration of ketamine during TMS allowed for higher intensities than would otherwise be tolerated by patients.

Ayahuasca’s ‘afterglow’: improved mindfulness and cognitive flexibility in ayahuasca drinkers.

2020| Murphy-Beiner, A., Soar, K.

This study (n=48) investigates the ‘afterglow’ effects of ayahuasca, focusing on improved mindfulness and cognitive flexibility to study its psychological mechanisms using Five Facets Mindfulness Questionnaire (FFMQ), Experiences Questionnaire (EQ), Cognitive Flexibility Scale (CFS), Wisconsin Picture Card Sorting Task (WPCST) and Stroop tests. The study findings reported that further changes in cognitive flexibility in the ‘afterglow’ period do occur and also supports the therapeutic potential of ayahuasca to improve mindfulness for naïve and experienced ayahuasca users.

Might Microdosing Psychedelics Be Safe and Beneficial? An Initial Exploration

2019| Fadiman, J., Korb, S.

This diary study investigates the "safe and beneficial" use of psychedelics in small quantities (microdosing; 10 micrograms LSD) to improve positive moods by evaluating positive and negative emotional states using the PANAS checklist and written reports. The study showed that microdosing of a psychedelic in clinical and non-clinical populations improved health habits, increased energy, and improved work effectiveness. Furthermore, smaller samples demonstrated alleviation of symptoms in migraine headaches, traumatic brain injury, pre-menstrual syndromes (PMS), shingles, and other such conditions that have not been previously associated with psychedelic use.

Neurocognitive aspects of ketamine and esketamine on subjects with treatment-resistant depression: A comparative, randomized and double-blind study

2021| Abreu, N., Araújo-de-Freitas, L., Beanes, G., Cardoso, T. L., Correia-Melo, F. S., Echegaray, M. VF., França, R. J. A. F., Guerreiro-Costa, L. N. F., Jesus-Nunes, A. P., Lacerda, A. L. T., Leal, G. C., Lucchese, C., Magnavita, G., Marback, R. F., Mello, R. P., Mendonça-Filho, E., Quarantini, L. C., Rabanea, T., Santos-Lima, C., Souza-Marques, B., Teles, M., Vieira, F.

This randomized, double-blind, placebo-controlled study (n=54) finds that both esketamine and (racemic) ketamine improve cognition immediately and up to 7 days later for those suffering from depression (TRD). There were virtually no differences between both subgroups. The study found improvements in executive functions, processing speed, and more.

Improvement of functional neurological disorder after administration of esketamine nasal spray: a case report

2021| Arteaga-Henríquez, G., Ramos-Quiroga, J. A., Rodríguez-Urrutia, A., Soto-Angona, Ó., Vendrell-Serres, J.

This case study (n=1) presents the first known case of successfully treating functional neurological disorder (FND), concurrent with depression, with esketamine. The study suggests that (es)ketamine may be a possible tool in treating FND.

The Impact of Childhood Maltreatment on Intravenous Ketamine Outcomes for Adult Patients with Treatment-Resistant Depression

2019| Lijffijt, M., Mathew, S. J., O'Brien, B., Swann, A. C., Wells, A.

This open-label study (n=115) found that ketamine improved depression (TRD) symptoms and especially for those with childhood trauma. It is hypothesized that the ability of ketamine to block trauma-associated behavioral sensitization is the mechanism through which this happens.

Long-Term Efficacy of Combination Therapy of Transcranial Magnetic Stimulation with Ketamine for Patients with Treatment-Resistant Depression

2021| Best, S. R. D., Haustrup, N., Pavel, D. G.

This retrospective review (n=28) investigated the clinical benefits of combining two therapies, repetitive transcranial magnetic stimulation (rTMS) and ketamine infusion (together CTK), for patients with treatment-resistant depression (TRD). The review found that all 28 patients experienced significant and enduring (two years) decreases in their depressive moods post the CTK therapy. The review also called for further research into method optimization and randomized controlled trials.

Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter

2018| de la Torre, R., de Sousa Fernandes Perna, E. B., Farré, M., Kuypers, K. P. C., Ramaekers, J. G., Theunissen, E. L., Xicota, L.

The placebo-controlled pooled study (n=63) investigates the role of 5-HTTLPR polymorphism, a part of the gene that codes for the serotonin transporter in the effects of MDMA (75 mg and placebo). The study found that those who are homozygous (two identical copies, the 'l-group') experienced more anxiety, and females within this group experienced a lowering of their depression scores. The study thus concludes there are gender and genotype differences in the effects of MDMA.

Ketamine Modulates the Neural Correlates of Reward Processing in Unmedicated Patients in Remission from Depression

2021| Abrão, J., Curran, H. V., Furey, M., Hawkins, P. C. T., Kotoula, V., Mackes, N., Mazibuko, N., Mehta, M. A., Stringaris, A.

This double-blind, placebo-controlled study (n=37) found that ketamine improved responses to rewards two hours after depressed patients had received ketamine (35mg/70kg) treatment. This correlated with neurological observations (increases in activation of NAc, the putamen, the insula, and the caudate).

Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties

2018| Aubee, J. I., Csoka, A. B., Getachew, B., Schottenfeld, R. S., Thompson, K. M., Tizabi, Y.

This animal study investigated ketamine (2.5 mg/kg) interactions with gut-microbiota in rats to understand its antidepressant and anti-inflammatory properties. The data concluded that there are some antidepressant and anti-inflammatory effects of ketamine treatment through its interaction with specific gut bacteria such as Lactobacillus, Turicibacter, and Sarcina and confirmed the usefulness of microbiome as a target for therapy using ketamine for some of its anti-inflammatory effects for specific inflammatory diseases including Irritable bowel syndrome (IBS). The study called for more detailed investigations of the interaction of microbiome with central mediators of mood and/or inflammatory disorders.

Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment‐resistant depression

2018| Cusin, C., Debattista, C., Fava, M., Flynn, M., Freeman, M. P., Hock, R. S., Hoeppner, B., Ionescu, D. F., Iosifescu, D. V., Mathew, S. J., Papakostas, G. I., Salloum, N. C., Sanacora, G., Trivedi, M. H.

This multisite, double-blind, placebo-controlled study (n=99) evaluated the effect of ketamine (3.5 - 35 mg/70kg) versus midazolam (3.15 mg/70kg) in anxious versus non-anxious unipolar treatment‐resistant depression (TRD). The pilot results concluded that there was no significant effect found between both groups. In contrast to traditional antidepressants, the effects of ketamine may be similar in both anxious and non-anxious TRD subjects.

Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial

2019| da Silva, F. S., de Almeida, R. N., de Araujo, D. B., de Menezes Galvão, A. C., dos Santos Silva, E. A., Galvão-Coelho, N. L., Lobão-Soares, B., Maia-de-Oliveira, J. P., Palhano-Fontes, F.

This placebo-controlled, double-blind randomized trial study (n=73) investigated the impact of BDNF (a protein related to the growth of neurons) on patients with depression who were administrated ayahuasca. The trial results observed a potential link between the changes in serum BDNF levels and the antidepressant effects of ayahuasca and also supported using psychedelics as an antidepressant.

Acute effects of ayahuasca in a juvenile non-human primate model of depression

2019| da Silva, F. S., Galvão-Coelho, N. L.

This animal study (n=15) investigated the efficacy of ayahuasca (0.6mg DMT, 3.1mg harmine, 0.4mg harmaline, and 0.34mg tetrahydroharmine /300g) to treat depressed marmoset monkeys exposed to 8 weeks of social isolation. They found that ayahuasca reduced scratching and depression-like behaviors, increased the feeding rate, and restored body weight and fecal cortisol to baseline levels, particularly within male monkeys.

Effects of Ketamine on Brain Activity During Emotional Processing: Differential Findings in Depressed Versus Healthy Control Participants

2019| Evans, J., Furey, M., Nugent, A. C., Reed, L. J., Szczepanik, J. E., Zarate, C. A.

This double-blind, placebo-controlled study (n=57) investigated ketamine’s effects on brain activity (BOLD) during an emotional processing task where fMRI of participants with depression (MDD) showed greater activity than healthy participants. After ketamine treatment, the depressed participants showed similar levels of brain activity, suggesting a normalization of function during emotional processing.

Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats

2019| Banks, M. L., Leggett, E., Moerke, M. J., Negus, S. S., Sakloth, F., Townsend, E. A.

This rodent study (2019) evaluated the acute effects of LSD on intracranial self-stimulation (ICSS), an operant conditioning reward measure. It found that acute LSD treatment did not alter its own ICSS depressant and the likelihood of methamphetamine abuse effects.

Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder

2019| Krystal, J. H., Petrakis, I. L., Yoon, G.

This open-label pilot study (n=5) investigated the use of naltrexone pretreatment (380 mg) with ketamine infusions (35mg/70kg, 4 infusions over 4 weeks) for depression and found that it does not interfere with ketamine's antidepressant effects. On the contrary, the study found that it might help in treating co-morbid alcohol use disorder and called for pre-clinical research to further understand these results, also in light of earlier conflicting research.

Chronic, Intermittent Microdoses of the Psychedelic N, N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents

2019| Benson, C. J., Cameron, L. P., DeFelice, B. C., Fiehn, O., Olson, D. E.

This animal study (n=35) investigated the effects of microdosing DMT (1mg/kg) in rats and found that a chronic (∼2 months), intermittent (every third day) microdosing regimen facilitated fear extinction learning and reduced depressive immobility in the forced swim test without producing the anxiety-like effects characteristic of a high dose.

Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial

2019| Akeju, O., Alpert, J. E., Baer, L., Bentley, K. H., Brown, E. N., Cusin, C., Dording, C., Eikermann, M., Fava, M., Ionescu, D. F., Mischoulon, D., Nock, M. K., Pavone, K. J., Petrie, S. R., Swee, M. B., Taylor, N.

This randomized, double-blind, placebo-controlled study (n=26) investigated the efficacy of ketamine (35mg/70kg) treatment for patients with severe depression and found that, in contrast to other studies, ketamine did not outperform placebo in terms of short- or long-term antidepressant or antisuicidal efficacy.

Self-Rated Effectiveness of Microdosing With Psychedelics for Mental and Physical Health Problems Among Microdosers

2019| Dolder, P. C., Hutten, N. P. W., Kuypers, K. P. C., Mason, N. L.

This survey study (n=410) showed that those with mental & physical health problems self-rated the effectiveness of microdosing as higher than conventional treatments in regards to ADHD/ADD and anxiety. They rated it as less effective than a high dose of psychedelics.

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression

2021| Barnes, L., Bolzenius, J. D., Brown, F., Cheng, W. W. L., Conway, C. R., Espejo, G. D., Gibbons, S., Gott, B., Jain, N., Janski, A., Komen, H., Lessov-Schlaggar, C. N., Nagele, P., Nguyen, T., Palanca, B. J. A., Salloum, N. C., Xiong, W., Yee, B., Zorumski, C. F.

This randomized, within-subjects, placebo-controlled, phase 2 clinical study (n=24) investigated the efficacy of nitrous oxide (25% air concentration) treatment for patients with depression and found that 25% nitrous oxide has comparable antidepressant efficacy to 50% nitrous oxide but with fewer adverse side effects.

Ceremonial Ayahuasca in Amazonian Retreats—Mental Health and Epigenetic Outcomes From a Six-Month Naturalistic Study

2021| Butler, M., Davies, M., Dempster, E. L., Morgan, C. J. A., Netzband, N., Rucker, J., Ruffell, S. G. D., Tsang, WF., Tófoli, L.F., Young, A. H.

This open-label (naturalistic) study (n=63) found that participants in ayahuasca retreats improved in scores of mental health (depression, anxiety, self-compassion), these effects lasted and were even somewhat improved at the 6-month follow-up. A study of participant's epigenetic data didn't yield conclusive results.

Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats

2017| Hao, X., Luo, J., Wang, Z., Ye, G., Zhu, X.

This animal study (n=72) investigated the molecular mechanisms underlying the antidepressant efficacy of ketamine (10, 25, and 50 mg/kg) and found that it may be partially attributed to the upregulation of excitatory amino acid transporters (EAATs) which enhance the reuptake of extracellular glutamate in the hippocampus of depressive-like rats.

Rapid effectiveness of intravenous ketamine for ultraresistant depression in a clinical setting and evidence for baseline anhedonia and bipolarity as clinical predictors of effectiveness

2018| Baker, G., Dursun, S., Lind, J., Thomas, R. K.

This retrospective, open-label, database study (n=50) examined the efficacy of ketamine (35mg/70kg) treatment for patients with ultra-resistant depression and found that baseline anhedonia and bipolar disorder strongly predicted treatment response (44%) and the rate of symptom remission (16%) across participants.

Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression

2018| Chen, L., Li, H., Li, M., Liu, W., Ning, Y-P., Wang, C., Zhan, Y.

This open-label study (n=84) found that 6 ketamine (35mg/70kg) infusions over 12 days led to cognitive improvements (speed of processing, verbal learning) in those with depression. The improvements were mediated by the level of improvement in depressive symptoms. Those with a higher baseline of visual learning had the greatest antidepressant response.

The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

2017| Abdallah, C. G., Coplan, J. D., Gupta, S., Jackowski, A., Mao, X., Mathew, S. J., Salas, R., Sato, J. R., Shungu, D. C.

This open-label cohort study (n=76) examined the effects of ketamine (35mg/70kg) on gray matter enlargement in relation to glutamate-based and non-glutamate-based abnormalities in patients with depression. They found that patients with non-glutamate-based depression exhibited an enlarged Nucleus Accumbens and that ketamine treatment leads to the rapid reduction in Nucleus Accumbens and an enlargement of the hippocampus only within patients who achieve remission of their depressive symptoms.

Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

2018| Benson, C. J., Cameron, L. P., Dunlap, L. E.

This study in rats with DMT found that it reduced anxiety by extinguishing of cued fear memory and reduces immobility in the forced swim test (a proxy for depression).

Sub-acute and long-term effects of ayahuasca on affect and cognitive thinking style and their association with ego dissolution

2018| Broers, N. J., Kuypers, K. P. C., Mason, N. L., Ramaekers, J. G., Riba, J., Toennes, S. W., Uthaug, M. V., van Boxtel, M., van Oorsouw, K.

This longitudinal study (n=57) investigated the effects of ayahuasca and found improved convergent thinking/creativity, decreased ratings of depression and stress up to four weeks later. These changes were significantly correlated with the level of ego dissolution experienced during the acute trip/ceremony.

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

2017| Abdallah, C. G., Averill, C., Averill, L. A., Baldwin, P. R., Krystal, J. H., Mathalon, D. H., Mathew, S. J., Salas, R.

This cohort study (n=51) found evidence for the hypothesis that ketamine normalizes prefrontal dysconnectivity. The first part of the study showed an increase in activity in the prefrontal global signal regression after ketamine (35mg/70kg) administration (which was lower in those with depression).

Disentangling the association of depression on the anti-fatigue effects of ketamine

2019| Ballard, E. D., Farmer, C. A., Kadriu, B., Saligan, L. N., Zarate, C. A.

This analysis of earlier data investigated of ketamine's (35mg/70kg) anti-fatigue effects (it significantly improves fatigue scores) could be separated from the anti-depressant (amotivation and depressed mood) effects. The study found that the effect was completely explained by this. In other words, the anti-depressant effects also caused the anti-fatigue effects.

Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial

2021| Bourque, S. L., Ceccherini-Nelli, A., Gragasin, F. S., Moreau, C., Nanji, J. A., Sivapalan, S., Woolsey, A. J.

This randomized, double-blind, placebo-controlled study investigated the efficacy of using low-dose ketamine (35mg/70kg) as an anesthetic adjunct to propofol during electroconvulsive therapy (ECT) for treating patients with depression (MDD). The addition of ketamine did not alter the antidepressant efficacy or the hemodynamics of electroconvulsive therapy, although it may be useful for reducing the dose requirements of propofol anesthesia.

Low-dose ketamine for treatment resistant depression in an academic clinical practice setting

2017| Boggie, D., Feifel, D., Lee, K., Malcolm, B.

This open-label retrospective study (n=41) evaluated the efficacy and safety of intravenous ketamine (35mg/70kg) infusion in a sample of patients who had treatment-resistant depression (TRD) and were being treated in a ‘naturalistic’ clinical context. Low-dose ketamine was efficacious and generally well-tolerated in the sample population, as participants reported improvements in depressive symptoms with a 53.7% response rate 24 hours post-infusion.

Cross-sectional associations between lifetime use of psychedelic drugs and psychometric measures during the COVID-19 confinement: A transcultural study

2021| Alcázar-Córcoles, M. A., Bouso, J. C., Dos Santos, R. G., Hallak, J. E., Ona, G., Révész, D., Rocha, J. M., Rossi, G. N.

This survey study (n=2,974) investigated the relationship between lifetime psychedelic use, personality traits, and mental health during the COVID-19 confinement, and found that regular use was associated with less psychological distress, less peritraumatic stress, and more social support. Psychedelic drug users also scored higher on the novelty-seeking and self-transcendence scales, but lower on cooperativeness.

Antisuicidal Response Following Ketamine Infusion Is Associated With Decreased Nighttime Wakefulness in Major Depressive Disorder and Bipolar Disorder

2017| Ballard, E. D., Bernert, R. A., Duncan, W. C., Luckenbaugh, D. A., Machado-Vieira, R., Niciu M. J., Park L. T., Richards E. M., Voort, J. L. V., Zarate, C. A.

This open-label study (n=34) investigated the effects of ketamine (35mg/70kg) on suicidal ideation and sleep rhythm in patients with (bipolar) depression and found that patients with less post-infusion nocturnal wakefulness exhibited an antisuicidal response to ketamine, compared to patients who were wakeful at night and continued suicidal ideation.

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

2018| Cui, Y., Dong, Y., Hu, H., Ma, S., Ni, Z., Sang, K., Yang, Y.

This animal study (n=500) investigated the neural circuitry underlying the antidepressant efficacy of ketamine (10 - 25mg/kg) in rodents and found that it blocks the activity of the lateral habenula, a network that normally inhibits reward processing, whose inhibition is in turn unblocked via ketamine.

A Single Dose Of Ayahuasca Modulates Salivary Cortisol In Treatment-Resistant Depression

2018| Adams, T.

This randomized double-blinded placebo-controlled between-subjects study (n=71) investigated the effects of ayahuasca (23.52mg DMT, 130.2mg harmine, 16.8mg harmaline, 84mg tetrahydroharmine /70kg) on salivary and plasma cortisol levels in patients with depression compared to healthy controls. Ayahuasca restored the corticosteroid insufficiency of depressed patients and increased their cortisol response to that of healthy controls.

Rapid antidepressant effect of S-ketamine in schizophrenia

2018| Bartova, L., Dold, M., Kasper, S., Milenkovic, I., Papageorgiou, K., Weidenauer, A., Willeit, M., Winkler, D.

This open-label case study (n=1) describes a patient with schizophrenia whose treatment regimen was augmented with a ketamine (25mg) infusion to alleviate her symptoms of depression and suicidal ideation (SI). Her symptoms underwent a robust and sustained remission after the infusion, without any accompanying psychotic or dissociative phenomena.

Ketamine normalizes brain activity during emotionally valenced attentional processing in depression

2018| Evans, J., Furey, M., Nugent, A. C., Reed, L. J., Szczepanik, J. E., Zarate, C. A.

This double-blind, placebo-controlled, crossover study (n=59) investigated how ketamine (35mg/70kg) affects the brain function of patients with depression compared to healthy controls, during the attentional processing of emotional stimuli. They found that depressed patients and healthy controls exhibited differences in the activation of the fronto-cingulate area during emotional processing and that this variation was normalized by ketamine, such that post-infusion brain activity in patients depression resembled that of healthy controls under the influence of placebo.

Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions

2018| Dunlop, B. W., Edwards, J. A., Galendez, G. C., Garlow, S. J., Job, G. P., McDonald, W., Reiff, C. M., Riva-Posse, P., Saah, T. C.

This retrospective open-label study (n=66) assessed the blood pressure safety profile of subanesthetic ketamine (35mg/70kg) infusion for patients with depression. Although hypertensive patients had higher blood pressure peaks during the infusions, the overall changes in blood pressure were small, well-tolerated, and clinically insignificant.

Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression

2018| Ballard, E. D., Brutsche, N. E., Farmer, C. A., Jaso, B. A., Luckenbaugh, D. A., Niciu, M. J., Park, L. T., Shovestul, B. J., Zarate, C. A.

This follow-up study (n=126) investigated whether the antidepressant effects of ketamine (35mg/70kg) were related to dissociative symptoms experienced by patients with (bipolar) depression, and found that the subjective effects of depersonalization were most closely related to the antidepressant response.

Changes in self-rumination and self-compassion mediate the effect of psychedelic experiences on decreases in depression, anxiety, and stress

2021| Fauvel, B., Piolino, P., Strika-Bruneau, L.

This online survey study (n=164) investigated how psychedelic-induced mystical experiences improve depression, anxiety, and stress, and found that these effects are partially mediated through decreased self-rumination and increased self-compassion.

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

2014| Brallier, J., Burdick, K. E., Chang, L. C., Charney, D. S., Foulkes, A., Iosifescu, D. V., Levitch, C. F., Mathew, S. J., Murrough, J. W., Perez, A. M.

This randomized, double-blind, active placebo-controlled study (n=62) investigated the neurocognitive and antidepressant effects of ketamine (35 mg/70kg) or midazolam (3.15mg/70kg) compared to the benzodiazepine anesthetic midazolam in patients with depression. Neurocognitive performance improved independently of treatment condition or change in depression severity due to learning, which indicates an absence of adverse effects of ketamine on neurocognitive functioning in contrast to electroconvulsive therapy which impacts memory.

Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy prolong the therapeutic effects of single ketamine infusion on post-traumatic stress disorder and comorbid depression: a pilot randomized, placebo-controlled, crossover clinical trial

2017| Goldberg, M., Moaddel, R., Parikh, T., Pradhan, B. K., Pumariega, A. J., Sabia, M., Torjman, M. C., Wainer, I. W.

This randomized, placebo-controlled, cross-over clinical pilot study (n=10) investigated the antidepressant efficacy of ketamine (35mg/70kg) infusion combined with Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy for patients with PTSD. Ketamine-assisted TIMBER therapy increased the duration of the sustained antidepressant response, as evidenced by improvement of depressive symptoms after switching from the placebo into ketamine condition.

A single infusion of ketamine improves depression scores in patients with anxious bipolar depression

2014| Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J., Richards, E. M., Zarate, C. A.

This randomized, double-blind, placebo-controlled, crossover, within-subjects study (n=36) investigated the effects of ketamine (35mg/70kg) treatment for anxious and non-anxious bipolar patients. Ketamine rapidly reduced symptoms of depression in patients with anxious bipolar depression to the same extent as those without anxiety.

Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety

2014| Ameli, R., Brutsche, N. E., Furey, M., Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J., Richards, E. M., Vande Voort, J. L., Zarate, C. A.

This post-hoc meta-analysis (n=133) examined the relationship between the antidepressant efficacy of intravenous ketamine (35mg/70kg) and its effects on suicidal ideation (SI) among patients with depression. Ketamine increased the patient's wish to live and decreased their wish to die, and these reductions in suicidal ideation independent of reductions in depressive and anxiety symptoms.

Acute antidepressant effect of ayahuasca in juvenile non-human primate model of depression

2018| da Silva, F. S., de Araujo, D. B., de Paula Soares Rachetti, V., de Sousa Junior, G. M., de Sousa, M. B. C., dos Santos Silva, E. A., Galvão-Coelho, N. L., Maia-de-Oliveira, J. P., Soares, B. L.

This vehicle-controlled animal study (n=15) investigated the antidepressant effects of ayahuasca (0.6mg DMT, 3.1mg harmine, 0.4mg harmaline, 0.33mg tetrahydroharmine /300g body weight) in juvenile marmoset monkeys exposed to chronic social isolation for 8 weeks prior. Depressive-like behaviors and changes in body weight and cortisol levels were ameliorated by a single dose of ayahuasca that rapidly induced long-lasting behavioral and physiological improvements.

Ketamine Use for Suicidal Ideation in the General Hospital: Case Report and Short Review

2018| Baup, E., Lefebvre, D., Lemogne, C., Limosin, F., Passeron, A., Rieutord, M., Seigneurie, A. S., Thauvin, I., Vulser, C., Vulser, H.

This case report (n=1) describes an anorexic patient who was treated with repeated dose ketamine (0.5mg/kg, 20mg) following a suicide attempt and persevering suicidal ideation (SI). Although the first dose had little effect, the second dose administered 2 weeks after led to a dramatic decrease in depression, hopelessness, and suicidal ideation.

Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial

2014| Conway, C. R., Cristancho, P., Duma, A., Gebara, M. A., Janski, A., Kopec, M., Miller, J. P., Nagele, P., Panagopoulos, V. N., Parsoei, A., Walker, M., Zorumski, C. F.

This double-blind, placebo-controlled, within-subjects proof-of-concept study (n=20) investigated the antidepressant efficacy of inhaled nitrous oxide (50/50 nitrous oxide/oxygen vs. 50/50 nitrogen/oxygen) in patients with treatment-resistant depression (TRD). Nitrous oxide resulted in treatment response in 20% of patients and symptom remission in 15%, an effect size comparable to that of ketamine.

Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling

2014| Buchborn, T., Grecksch, G., Höllt, V., Schröder, H.

This study (2014) found that repeated LSD administration to rats exhibits an anti-depressive effect in the animals, which the authors discuss in terms of a rebalancing of neurological signaling.

Psychedelic drug assisted psychotherapy in patients with terminal cancer

1972| Goodman, L. E., Grof, S., Kurland, A. A., Pahnke, W. N.

This early study (1972) describes the use of LSD-assisted psychotherapy for patients with terminal cancer. Results suggest significant improvements on various clinical assessments.

Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features

2003| Bleich, A., Gelkopf, M., Nachshon, H., Rudinski, D., Skladman, I.

This open-label study (n=16) suggests that high-potency benzodiazepines like clonazepam (2mg/day for 60 days) may be helpful in alleviating Hallucinogen Persisting Perception Disorder (HPPD). The patients reported relief up to four months after treatment. Do note that there was no control group in this study.

Exploring the therapeutic potential of Ayahuasca: acute intake increases mindfulness-related capacities

2015| Barker, S., Elices, M., Feilding, A., Franquesa, A., Friedlander, P., Pascual, J. C., Riba, J., Soler, J.

This observational study (n=25) found that ayahuasca intake led to significant increases in mindfulness comparable to those obtained after extensive mindfulness practice. The authors argue that this effect may be the mediating factor responsible for ayahuasca's observed therapeutic potential.

Low-dose ketamine for treatment resistant depression in an academic clinical practice setting

2017| Boggie, D., Feifel, D., Lee, K., Malcolm, B.

This retrospective observational study (n=41) suggests that ketamine (35mg/70kg) as a treatment for treatment-resistant depression (TRD) may be effective despite the high rates of comorbidity (multiple medical conditions in one patient) observed in patients groups outside the lab.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

2021| Amar, S., Amiaz, R., Bogenschutz, M. P., Brown, R., Carlin, S. C., Coker, A., de Boer, A., Doblin, R., Emerson, A., Garas, W., Gelfand, Y., Gorman, I., Hamilton, S., Hapke, E., Harrison, C., Klaire, S. S., Kleiman, S., Lilienstein, A., Marta, C. J., Matthews, R., Mitchell, J., Mithoefer, A. T., Mithoefer, M. C., Nicholas, C. R., Ot’alora G, M., Paleos, C., Parker-Guilbert, K., Poulter, B., Quevedo, S., Shannon, S., Tzarfaty, K., van der Kolk, B., Wallach, Y., Wang, J. B., Wells, G., Woolley, J. D., Worthy, R., Yazar-Klosinski, B.

This double-blind, placebo-controlled study (n=90) finds that MDMA-assisted therapy (8-120mg) is effective (d=.91, large effect size) in the treatment of PTSD. 67% of those in the MDMA-group no longer qualified for PTSD (vs 32% for the therapy-only group). This study is part of the Phase 3 trial to get MDMA approved by the FDA.

A continuum hypothesis of psychotomimetic rapid antidepressants

2021| Haarsma, J., Harmer, C. J., Tamm, S.

This hypothesis article (2021) proposes that psychedelics (and sleep deprivation) are acute antidepressants that fall on a continuum of increasing the flexibility of prior expectations (top-down hierarchy). The article ends with suggestions for experiments to test this hypothesis.

Lifetime use of psychedelics is associated with better mental health indicators during the COVID-19 pandemic

2021| Cavanna, F., Cuiule, J., Di Tella, R., González, P., Milano, V., Pallavicini, C., Tagliazucchi, E.

This survey (n=5618) found that those who used psychedelics (32% of the sample) had increased positive affect and more resilient personality traits (e.g. plasticity) during the COVID-19 pandemic.

The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action

2020| Andrashko, V., Bravermanová, A., Brunovský, M., Bušková, J., Dudysová, D., Froese, T., Horacek, J., Janků, K., Kopřivová, J., Korčák, J., Mander,B. A., Páleníček, T., Saifutdinova, E., Šmotek, M., Tylš, F., Viktorinová, M., Zach, P.

This randomized, double-blind, placebo-controlled, within-subjects study (n=17) investigated the effects of psilocybin (18.2mg/70kg) on brain rhythms during sleep and found that it increased the transition period from wakefulness to REM sleep and reduced the duration of the REM period. These results are in line with the effects of other antidepressants and diametrically opposed to biomarkers of depression that include shortened wakefulness to REM transitions and increased REM duration and density.

Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder

2014| Feder, A., Murrough, J. W., Parides, M. K.

This randomized, double-blind, active placebo-controlled study compared the efficacy of ketamine (35mg/70kg) and midazolam (3.15mg/70kg) for the treatment of patients with depressive symptoms associated with chronic PTSD. They found a rapid reduction in symptom severity following intravenous ketamine infusion.

Distinct trajectories of antidepressant response to intravenous ketamine

2021| Kim, Y. S., Lee, J., Lijffijt, M., Mathew, S. J., Murphy, N., Ramakrishnan, N., Swann, A. C., Wells, A.

This open-label study (n=328) found that people who were depressed, for those with childhood physical abuse responded best to ketamine (48mg/70kg) treatment. This analysis was done retrospectively and the analysis consisted of breaking the group in three parts (responders, non-responders, responders with lower initial depression scores).

Predictive value of heart rate in treatment of major depression with ketamine in two controlled trials

2021| Andrashko, V., Brunovský, M., Horacek, J., Meyer, T., Olbrich, S., Seifritz, E.

This open-label study (n=51) found that a large increase in heart rate (HR) and -variability (HRV) predicted better outcomes for those suffering from depression (MDD) after administration of ketamine.

Influence of Context and Setting on the Mental Health and Wellbeing Outcomes of Ayahuasca Drinkers: Results of a Large International Survey

2021| Bouso, J. C., Galvão-Coelho, N. L., Horák, M., Perkins, D., Sarris, J., Schubert, V., Simonová, H., Tófoli, L.F.

This survey (n=6877) of ayahuasca drinkers investigated the influence of context and setting on mental health and wellbeing outcomes. A combination of motivation, ceremony, and support variables predict these outcomes in a new model proposed in this paper.

A Qualitative Study of Intention and Impact of Ayahuasca Use by Westerners

2021| Bathje, G. J., Fenton, J., Hill, L. C., Pillersdorf, D.

This qualitative interview study (n=41) found that ayahuasca use by Westerners (in group settings), led to many sustained positive outcomes. These related to mental health, substance use, interpersonal relationships, and also creativity, physical health, connection to nature. Two participants indicated problematic experiences (sexual assault, enduring psychotic symptoms).

Clinical Studies of Lysergic Acid Diethylamide

1986| Anderson, E. W., Rawnsley, K.

This early clinical study (1954) investigated the dose-range effects of LSD (10-600μg) administered to patients and clinical staff (n=23) across 54 different research sessions and found that its effects entail highly potent perceptual alterations that are sensitive to the environment and variable across different individuals. They also note the emergence of phenomena such as enhanced sexual arousal and ego-dissolution and highlight its utility at illuminating basic personality structures but remain inconclusive as to whether it has therapeutic benefit in response to continued administration.

Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects

2018| Ballard, E. D., Brutsche, N. E., Gould, T. D., Moaddel, P. J., Nugent, A. C., Park, L. T., Zarate, C. A.

This double-blind, placebo-controlled, brain imaging study (MEG; n=60) found that ketamine (35mg/70kg) produced different effects in healthy (n=25) and depressed (MDD; n=35) subjects. Both had significant improvement in scores of depression, increases in resting gamma power, those with MDD and lower initial gamma scores and higher scores after ketamine improved most.

Symptom specificity of ayahuasca's effect on depressive symptoms

2021| Altman, B. R., Earleywine, M., Gilbert, C. S., Mian, M. N.

This retrospective survey study (n=120) found that ayahuasca improved specific depressive symptoms (CESD-10) namely hope, depressed mood, and happiness, more than other symptoms such as cognitive, interpersonal, sleep, loneliness, and focusing.

Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression

2021| Lan, X-F., Ning, Y-P., Wang, C-Y., Yan, S., Zhang, B., Zheng, W., Zhou, S-M., Zhou, Y-L.

This open-label study (n=94) finds that baseline plasma BDNF concentrations (a protein related to nerve growth) correlate with ketamine (6 infusions, 35mg/70kg) antidepressant effects (MADRS).

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)

2020| Canuso, C. M., Drevets, W. C., Fu, D. J., Hough, D., Ionescu, D. F., Lane, R., Lim, P., Manji, H., Sanacora, G.

This placebo-controlled, double-blind study, phase 3 study (n=226) compared esketamine (84mg, nasal, 2xp/w for 4w) with a placebo spray and found esketamine to be effective in lowering depression scores (MADRS) for those suffering from depression (MDD) and suicidal ideation (SI). Scores on a measure of SI was, however, not significantly different between the two groups.

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

2017| Ardalan, M., Nyengaard, J. R., Rafati, A. H., Wegener, G.

This vehicle-controlled animal study (n=24) investigated the effects of esketamine (4.5mg/0.3kg) on astrocyte plasticity in the hippocampus of a depression-model rat strain. Results indicate that ketamine can rapidly modify the shape of astrocytes (sub-type of glial cells) so that they can optimally modulate the synaptic micro-environment, neurogenesis, and vascularization, which is otherwise impaired under depression.

A qualitative and quantitative account of patient’s experiences of ketamine and its antidepressant properties

2021| Anderson, C., Chacko, E., Chen, J., French, A., Hay, J., Jung, S., Malpas, G., McMillan, R., Muthukumaraswamy, S., Ponton, R., Rajan, A., Spriggs, M. J., Sumner, R. L., Sundram, F.

This randomized, double-blind, active placebo-controlled, crossover study (n=32) investigated the antidepressant efficacy of ketamine (31mg/70kg) by using quantitative and qualitative assessments of its long-term effects and acute psychedelic experience. Rapid improvements in depressive symptoms correlated with higher scores on the spirituality, experience of unity, and insight subscales of the altered states of consciousness questionnaire (11D-ASC), but were not sustained beyond two weeks.

Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression

2017| Gruca, P., Lason-Tyburkiewicz, M., Papp, M., Willner, P.

This vehicle-controlled rodent study (n=16) compared the antidepressant and anxiolytic effects of ketamine (5, 10, 15 or 30 mg/kg) to the antidepressant imipramine (10 mg/kg), using chronic exposure to mild stress as a depression model and assessing their cognitive capacity of novel object recognition and their natural aversion to open spaces. Results indicated a sustained antidepressant-like effect of ketamine at an optimum dose of 10 mg/kg, which reversed the anxiogenic and dyscognitive effects of chronic mild stress exposure much faster than the classical antidepressant imipramine.

Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression

2016| He, H., Huang, X., Jiang, M., Li, Q., Wang, Z., Zhang, C., Zhang, M., Zhong, X.

This randomized, double-blind, active placebo-controlled study (n=90) compared the antidepressant efficacy between ketamine (56mg/70kg), the anesthetic propofol (56mg/70kg), and the combination of ketamine (35mg/70kg) plus propofol (35mg/70kg), within the context of pretreatment for electroconvulsive therapy for patients with treatment-resistant depression (TRD). Compared to the others, the ketamine group exhibited earlier improvements in depression, better seizure parameters and seizure quality in electroconvulsive therapy, and a lower degree of executive cognitive impairment, which highlights the usefulness of ketamine-assisted electroconvulsive therapy for treating depression.

Intravenous arketamine for treatment-resistant depression: open-label pilot study

2020| Bandeira, I. D., Bezerra, M. L. O., Caliman-Fontes, A. T., Correia-Melo, F. S., Dias-Neto, A. L., Guerreiro-Costa, L. N. F., Jesus-Nunes, A. P., Lacerda, A. L. T., Leal, G. C., Lima, C. S., Loo, C., Marback, R. F., Marques, B. L. S., Mello, R. P., Quarantini, L. C., Sampaio, A. S., Sanacora, G., Silva, S. S., Telles, M., Turecki, G., Vieira, F.

This open-label study (n=7) study investigated the antidepressant efficacy of (R-)ketamine (35mg/70kg), which has been implicated by animal studies to be more potent and longer-lasting compared to (S-)ketamine. Results demonstrate (R-)ketamine's ability to produce a fast and robust antidepressant effect in patients with depression, with potentially greater and longer-lasting effects, greater response rate, and a lower remission rate than effects reported for (S-)ketamine, although this study had a small sample size and lacked placebo-control.

Trial of Psilocybin versus Escitalopram for Depression

2021| Baker-Jones, M., Blemings, A., Carhart-Harris, R. L., Erritzoe, D., Giribaldi, B., Martell, J., Murphy, R., Murphy-Beiner, A., Nutt, D. J., Watts, R.

This double-blind placebo-controlled study (n=59) compared psilocybin (2x25mg; 3 weeks apart) to escitalopram (SSRI) over a six-week period and found large improvements in depression scores for those suffering from depression (MDD) in both groups. On the main measure of depression, the QIDS-SR-16, there was no significant difference between both groups. The study did find significant differences, favoring psilocybin, on the HAM-D-17, MADRS, avoidance, flourishing, wellbeing, and suicidality.

Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

2021| Cole, A. B., Hesselgrave, N., Thompson, S. M., Troppoli, T. A., Wulff, A. B.

This mice study found that the anti-depressant effects from psilocybin (1mg/kg) are possibly independent of the psychedelic/hallucinogen effects by pre-treating the mice with ketanserin (which blocks the acute effects) and finding similar anti-depressant effects as in the psilocybin only group (measured through activity patterns and synaptic action).

Acute cognitive effects of single-dose intravenous ketamine in major depressive and posttraumatic stress disorder

2021| Davis, M. T., DellaGiogia, N., Esterlis, I., Maruff, P., Pietrzak, R. H.

This open-label study (n=58) compared the effects of a single dose of ketamine (35-56.7mg/70kg) on the cognitive effects of those suffering from depression (MDD; n=14) or PTSD (n=15) and healthy control subjects (n=29). The study found acute declines in attention, executive function, and verbal memory. Only the effect on attention was larger in the patient groups. The baseline cognitive function of participants didn't predict clinical outcomes.

LSD-assisted psychotherapy and the human encounter with death

1972| Goodman, L. E., Grof, S., Kurland, A. A., Richards, W. A.

This early study (1972; n=31) on LSD-assisted psychotherapy (200-500µg) showed the promise of using psychedelics in combination with therapy. The participants of the study were diagnosed with cancer and received therapy/preparation before (10 hours) and after (1-2 hours). Of these patients, 9 (29%) significantly improved on scores of emotional/mental health.

A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

2016| Cooper, K., Daly, E. J., De Boer, P., Drevets, W. C., Fava, M., Fedgchin, M., Kurian, B., Lim, P., Manji, H., Murrough, J. W., Pinter, C., Sanacora, G., Shelton, R. C., Singh, J. B., Van Nueten, L., Winokur, A.

This multicenter, double-blind, randomized, placebo-controlled study (n=67) investigated the antidepressant effects of ketamine (35mg/70kg) in relation to the dose frequency administered to patients with depression (TRD). Results indicated that both a twice-weekly and thrice-weekly administration regimen maintained antidepressant efficacy over 15 days.

Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial

2021| Abrão, J., Guimarães, M. C., Guimarães, T. M., Hallak, J. E., Machado-de-Sousa, J. P.

This double-blind placebo-controlled between-subjects study (n=23) tested the antidepressant efficacy of inhaled nitrous oxide (50% N2O|50% O2 versus 100% O2) in patients diagnosed with major depression (MDD). Across multiple treatment sessions administered across a period of 4 weeks, there were significant reductions in depressive symptoms in the acute response to treatment and accumulatively across sessions.

Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine

2021| Chen, L., Grieco, S. F., Holmes, T. C., Johnston, K. G., Lai, C., Nelson, R. R., Qiao, X., Xu, X.

This rodent study (n=50) investigated the signaling pathways associated with the rapid antidepressant effects of ketamine (10mg/kg) and found a novel neural plasticity-based mechanism implicated in its acute and sustained effects.

A quantitative exploration of the relationships between regular yoga practice, microdosing psychedelics, wellbeing and personality variables

2021| Bettinson, S., Blatchford, E., Bright, S. J., Gringart, E.

This exploratory cross-sectional survey study (n=339) investigated differences in mood and wellbeing between samples of people who either microdose, practice yoga, or engage in neither, in light of personality trait differences in openness, neuroticism, and absorption. Microdosing and yoga practices exhibited complementary effects, as participants who practiced both had the highest absorption score, exhibited higher levels of wellbeing, and had less depression and anxiety, compared to people who either practiced yoga or microdosing, and participants recruited as controls. However, participants were recruited from different population samples, which may bias self-report, and lead to significant differences in age, gender, employment, and education between the conditions.

Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca

2020| Campos Braga, I., de Almeida, R. N., de Araujo, D. B., de Menezes Galvão, A. C., Galvão-Coelho, N. L., Lobão-Soares, B., Maia-de-Oliveira, J. P., Palhano-Fontes, F., Perkins, D., Sarris, J.

This double-blind, active placebo-controlled study (n=73) investigated the effects of ayahuasca (25.2mg/70kg of DMT, 130.2mg/70kg of harmine, 16.8 mg/70kg of harmaline, 84mg/70kg of tetrahydroharmine) on blood inflammatory biomarkers in patients with treatment-resistant depression (n=28) and healthy controls (n=45). Results indicate that 48 hours after treatment the concentration of the inflammatory biomarker CRP was reduced in response to ayahuasca but to placebo amongst both healthy volunteers and patients with depression and that improvements in the patients' depressive symptoms were correlated with this trend.

The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study

2016| Chen, M. H., Hong, C. J., Li, C. T., Lin, W. C., Liu, R. S., Su, T. P., Tu, P. C., Yang, B. H.

This double-blind placebo-controlled study (n=48) investigated the antidepressant efficacy of ketamine (14 or 35mg/70kg) in patients with depression and found evidence that its rapid antidepressant effects at 40 and 240 minutes post‐treatment were facilitated by glutamatergic neurotransmission in the prefrontal cortex.

Ketamine plus propofol-electroconvulsive therapy (ECT) transiently improves the antidepressant effects and the associated brain functional alterations in patients with propofol-ECT-resistant depression

2020| Chen, M., Chen, S., Ji, S., Jiang, D., Li, G., Li, J., Lin, X., Tian, H., Wang, L., Wang, W., Zhang, J., Zhu, J., Zhuo, C.

This open-label study (n=28) investigated whether ketamine (35mg/70kg) treatment prior to propofol-assisted electroconvulsive therapy (ECT) can improve clinical symptoms of depression. The addition of ketamine improved treatment, and this was accompanied by increased global functional connectivity density in the left temporal and subgenual anterior cingulated cortex and decreased functional connectivity strength within the default mode network for a period of 10 days. However, the remission of depressive symptoms only lasted 7 days.

Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients

2020| Aust, S., Bajbouj, M., Basso, L., Bönke, L., Grimm, S., Gärtner, M., Heuser-Collier, I., Otte, C., Wingenfeld, K.

This open-label between-subjects study (n=49) compared the antidepressant efficacy of serial R(-)ketamine treatment (35mg/70kg) versus electroconvulsive therapy (ECT) for patients with depression. Ketamine produced faster antidepressant effects and improved neurocognitive functioning, especially attention and executive functions, which implicate that it may be a more favorable treatment option in the short-term.

A rapid positive influence of S-ketamine on the anxiety of patients in palliative care: a retrospective pilot study

2020| Cordes, J., Falk, E., Grau, I., Kienbaum, P., Lutterbeck, M. J., Neukirchen, M., Schlieper, D., Schwartz, J., van Caster, P.

This retrospective pilot study (n=8) investigated whether the purified enantiomer S-ketamine (17.5mg/70kg) has a positive impact during the treatment of pain for patients within palliative care, and found that it alleviated psychological distress, depression, and anxiety.

Ketamine Treatment and Global Brain Connectivity in Major Depression

2016| Abdallah, C. G., Anticevic, A., Averill, C., Averill, L. A., Charney, D. S., Collins, K. A., DeWilde, K. E., Geha, P., Iosifescu, D. V., Murrough, J. W., Schwartz, J., Tang, C. Y., Wong, E.

This open-label, counterbalanced, between-subjects study (n=43) compared brain activity before and after ketamine (35mg/70kg) administration across healthy control and patients with major depression. The treatment normalized restored abnormally low brain connectivity levels in the prefrontal cortex of patients with depression, which may be indicative of a potential mechanism whereby ketamine restores synaptic dysconnectivity related to chronic stress and increased extracellular glutamate in the prefrontal cortex. The authors highlight the method of global brain connectivity with signal regression as a useful biomarker for quantifying treatment response to rapid-acting antidepressants.

The effect of ketamine on preventing postpartum depression

2021| Alipoor, M., Farahbakhsh, F., Kazemi, M., Loripoor, M., Sarkoohi, A.

This double-blind study (n=134) suggests that the usage of ketamine in the induction of a caesarian section may be helpful in preventing postpartum depression.

Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial

2016| Afarideh, M., Agah, E., Akhondzadeh, S., Arbabi, M., Ghajar, A., Jafarinia, M., Noorbala, A. A., Saravi, M. A., Tafakhori, A.

This double-blind study (n=40) compared the efficacy and safety of oral ketamine and diclofenac as treatments of mild to moderate depression over a 6-week treatment period and found that ketamine resulted in significant reductions of depression scores above those achieved by diclofenac.

A Double-Blinded, Randomized, Placebo-Controlled Sub-Dissociative Dose Ketamine Pilot Study in the Treatment of Acute Depression and Suicidality in a Military Emergency Department Setting

2016| Boche, B., Burger, J., Capobianco, M., Darracq, M. A., Lovern, R., McLay, R., Ross, E.

This placebo-controlled proof-of-concept study (n=10, 7 placebo) administered sub-dissociative doses of ketamine to military personnel experiencing depression and suicidal ideation (SI), and found that the ketamine infusion resulted in significant short-term improvement in two out of the three patients who received the drug.

Antidepressant effects of ketamine in depressed patients

2000| Anand, A., Berman, R. M., Cappiello, A., Charney, D. S., Heniger, G. R., Krystal, J. H., Oren, D. A.

This double-blinded, randomized, placebo-controlled, within-subjects study (n=7) investigated the antidepressant efficacy of a single dose of ketamine (35mg/70kg) in patients with depression and found significant improvements in depressive symptoms within 72 hours after infusion.

Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes

2021| Agin-Liebes, G. I., Davis, A. K., Lancelotta, R., Ramaekers, J. G., Uthaug, M. V.

This survey study (n=452) found that the use of mescaline led to improvements in scores on clinical conditions for those suffering from clinical conditions (anxiety 80%, depression 86%, PTSD & AUD 76%). Those who scored higher on acute mystical experience (MEQ30), ego dissolution, and psychological insight had larger improvement than those who scored lower.

A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats

2021| de Sousa Fernandes Perna, E. B., Fábregas, J. M., Kuypers, K. P. C., Mason, N. L., Ramaekers, J. G., Reckweg, J., Riba, J., Toennes, S. W., Uthaug, M. V., van Oorsouw, K.

This double-blind placebo-controlled study (n=30) controlled for expectation bias in a naturalistic ayahuasca ceremony. The use of ayahuasca led to more emotional empathy, but both groups improved as much on symptoms of depression, anxiety, and stress.

Ayahuasca: pharmacology, neuroscience and therapeutic potential

2016| Álvarez, E., de la Fuente Revenga, M., Domínguez-Clavé, E., Elices, M., Feilding, A., Friedlander, P., Pascual, J. C., Riba, J., Soler, J.

This review (2016) examines the pharmacology and neuroscience of ayahuasca, and preliminary findings which indicate the psychological mechanisms associated with its therapeutic benefits are similar to those of mindfulness-based therapy. Ayahuasca appears to enhance self-acceptance and decentering, which converges on evidence from neuroimaging studies that show activation in areas associated with emotional processing and memory formation, thereby enabling individuals to review emotional events with increased vividness and a heightened sense of “reality”. This suggests potential to treat trauma-related conditions and other disorders like borderline personality disorder.

Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

2016| Crippa, J. A., Dos Santos, R. G., Hallak, J. E., Osório, F. L.

This meta-analysis (2016) examines studies on the mental health effects of ayahuasca, harmine, and harmaline within humans and animals, and shows consistent evidence for its antidepressant and anxiolytic (anxiety) effects.

Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder

2015| Charney, D. S., Collins, K. A., DeWilde, K. E., Fields, J., Iosifescu, D. V., Mathew, S. J., Murrough, J. W., Phillips, M. L., Tang, C. Y., Wong, E.

This open-label between-subjects fMRI study (n=38) investigated the antidepressant effects of ketamine (35mg/70kg) with regard to changes in the neural correlates of emotional processing, 24 hours after infusion, in patients with major depression (n=18) compared to baseline measures from healthy volunteers (n=20). They found that ketamine rapidly increases brain responses to positive emotion, which correlated with increased connectivity of the right caudate during and improvement in depression severity.

A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

2020| Albott, C. S., Erbes, C., Lim, K. O., Shiroma, P. R., Thuras, P., Tye, S., Wels, J.

This randomized active placebo-controlled between-subjects study (n=54) compared the antidepressant efficacy of administering six consecutive ketamine infusions (35 mg/70kg) versus consecutive five midazolam infusions (3.15 mg/70kg) followed by a single ketamine infusion, over twelve days. While acute repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions, there was no significant difference in depression scores after the control grouped had received a single ketamine infusion.

Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice

2021| Beardsley, P. M., de la Fuente Revenga, M., González-Maeso, J., Guevara, C. A., Huntley, G. W., Lu, C., Naler, L. B., Saunders, J. M., Sierra, S., Toneatti, R., Wolstenholme, J. T., Zhou, Z., Zhu, B.

This placebo-controlled rodent study (n=10) investigated the epigenetic factors driving neuroplasticity and contextual fear extinction in response to the serotonergic hallucinogen DOI (2mg/kg). Using a transgenetic knockout mouse strain that lacked 5-HT2A receptors, this study demonstrates that this pathway is essential for inducing long-lasting alterations in frontal cortex gene expression and chromatin organization that outlast the acute antidepressant action of this psychedelic and its presence in the organism.

Self-blinding citizen science to explore psychedelic microdosing

2021| Blemings, A., Carhart-Harris, R. L., Erritzoe, D., Feilding, A., Kartner, L., Nutt, D. J., Rosas, F. E., Szigeti, B.

This self-blinding experiment (n=191) finds that the placebo and microdosing groups both experienced similar improvements in self-rated psychological well-being and cognitive function (e.g. mood, energy, creativity) after four weeks. This study provides more evidence that microdosing benefits can be attributed to expectancy (placebo) effects.

Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin

2020| Abdallah, C. G., Ahn, K-H., Averill, L. A., Duman, R. S., D’Souza, D. C., Formica, R., Goktas, S., Gueorguieva, R., Krystal, J. H., Purohit, P., Ranganathan, M., Sanacora, G., Sherif, M., Southwick, S. M.

This double-blind, randomized, placebo-controlled study (n=20) found that rapamycin (6mg, iv) extended the antidepressant effects (MADRS) of ketamine (35mg/70kg) at two weeks (41% higher response rate, 29% higher remission rate). This is contrasted to (animal/in vitro) studies that found opposing effects.

Neural correlates of change in major depressive disorder anhedonia following open-label ketamine

2015| Nutt, D. J.

This open-label study (n=52) investigated the effects of ketamine (35mg/70kg) with regard to the neural correlates related to the remission of anhedonia in major depressive disorder (MDD). Ketamine infusion rapidly reduced anhedonia, a trend that was sustained for three days and correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC).

Single, Fixed-Dose Intranasal Ketamine for Alleviation of Acute Suicidal Ideation. An Emergency Department, Trans-Diagnostic Approach: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial

2021| Domany, Y., McCullumsmith, C. B.

This double-blind placebo-controlled study study (n=30) with intranasal ketamine (40mg) found significant reductions in suicidal ideation (SI, 80 vs 33% remission) and depressive symptoms (MADRS) 4 hours after administration for those with SI in the emergency department.

Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder

2019| Wang, C-Y., Zheng, W., Zhou, Y-L.

This open-label study (n=77) examines the sustained effects of six consecutive ketamine infusions (0.5mg/kg over 40 min) in Chinese patients with major depressive disorder (MDD). Six ketamine infusions increased rates of response and remission when compared to a single-dose ketamine infusion in patients with MDD.

A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms

2019| Jurok, R., Kuchar, M., Kuypers, K. P. C., Lancelotta, R., Maryska, M., Mason, N. L., Páleníček, T., Rak, J., Ramaekers, J. G., Riba, J., Sulakova, A., Uthaug, M. V., van Oorsouw, K.

This open-label (naturalistic) study (n=42) with 5-MeO-DMT (smoked) found that it significantly reduced ratings of depression, anxiety, and stress. It also increased scores on mindfulness and life satisfaction. These effects correlated with higher ego dissolution and oceanic boundlessness during the acute experience.

People of color in North America report improvements in racial trauma and mental health symptoms following psychedelic experiences

2020| Davis, A. K., Grigas, P. C., Haeny, A. M., Sepeda, N. D., Sinnott, S., Williams, T. M., Xin, Y.

This survey study (n=313) suggests that psychedelic experiences (MDMA, LSD, psilocybin) could reduce symptoms of racial trauma. The participant, 30 days later, slowed moderate reductions in traumatic stress, depression, anxiety, and stress.

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

2013| Al Jurdi, R. K., Chang, L. C., Charney, D. S., Foulkes, A., Green, C. E., Iosifescu, D. V., Iqbal, S., Mathew, S. J., Murrough, J. W., Perez, A. M., Pillemer, S., Shah, A.

This rigorous randomized controlled trial (n=73) found that ketamine has rapid (24 hours) anti-depressant effects (MARDS) for those with treatment-resistant depression (TRD).

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

2012| Charney, D. S., Collins, K. A., Iosifescu, D. V., Mathew, S. J., Murrough, J. W., Parides, M. K., Perez, A. M., Pillemer, S., Rot, M. A. H., Stern, J.

This open-label study (n=24) found that repeated infusions of ketamine can sustain the rapid anti-depressant effect obtained after one infusion. Nevertheless, the effect of 6 infusions was only maintained for a median of 18 days.

Effects of ayahuasca on psychometric measures of anxiety, panic-like and hopelessness in Santo Daime members

2007| Cruz, A. P. M., Dos Santos, R. G., Landeira-Fernandez, J., Motta, V., Strassman, R. J.

This double-blind placebo-controlled study (2007; n=9) investigated state and trait anxiety, hopelessness, and panic under the acute influence of ayahuasca in long-term users. Results show decreases in hopelessness and panic, but no change in anxiety.

More realistic forecasting of future life events after psilocybin for treatment-resistant depression

2018| Carhart-Harris, R. L., Lyons, T.

This open-label study (n=30) found that psilocybin corrected pessimism biases in depressed patients and that this change in pessimism was significantly correlated with improvement in depressive symptoms.

Psychiatry’s next top model: cause for a re-think on drug models of psychosis and other psychiatric disorders

2013| Brugger, S., Carhart-Harris, R. L., Nutt, D. J., Stone, J. M.

This survey study (2013) compared five drugs on their ability to model a variety of psychiatric conditions. It found, among other results, that psilocybin was the best model for positive psychotic symptoms.

Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain

2011| Cesconetto, P., Ferraro, A. K., Quevedo, J., Ribeiro, K. F., Réus, G. Z., Souza, C. T., Stringari, R. B., Vitto, M. F.

This placebo-controlled animal study (n=135) investigated the possibility of synergistic interactions between antidepressant imipramine (10-20mg/kg) with ketamine (5-10mg/kg). The results indicate that co-administration of imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone.

The hidden therapist: evidence for a central role of music in psychedelic therapy

2018| Carhart-Harris, R. L., Evans, J., Feilding, A., Giribaldi, B., Kaelen, M., Nutt, D. J., Raine, J., Rodrigues, N. B., Roseman, L., Timmermann, C.

This open-label qualitative interview study (n=19) assessed the role of music during psychedelic therapy with psilocybin (25mg/70kg) for treatment-resistant depression. It identified a number of ways in which music influenced their experience, most frequently related to the intensification of emotions and mental imagery, and the music appeared to be a significant source of guidance, creating a sense of grounding, as well as a sense of carrying the listener into different psychological places.

Decreased mental time travel to the past correlates with default-mode network disintegration under lysergic acid diethylamide

2016| Carhart-Harris, R. L., Feilding, A., Kaelen, M., Nutt, D. J., Schloerscheidt, A. M., Speth, C., Speth, J.

This double-blind placebo-controlled study (n=20) investigated the effects of LSD (75 μg/70kg) in relation to participants' ability to mentally project themselves backwards and forwards in time, based on brain activity measures and subjective reports that were analyzed by six blinded qualitative proof raters. There were significantly fewer cases of mental time travel to the past under LSD, meaning that they were less likely to recollect aspects of the past autobiographical self, and this phenomenon was correlated with the decreased integrity of the Default Mode Network.

Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression

2013| Horacek, J., Klirova, M., Kohutova, B., Novák, T., Páleníček, T., Sos, P.

This double-blind, cross-over, placebo-controlled study (n=27) investigated the antidepressant and psychotomimetic effects of a single ketamine infusion (38mg/70kg) in patients diagnosed with major depressive disorder. Ketamine infusion induced acute psychotomimetic symptoms, which correlated with the alleviation of negative mood ratings and the betterment of depression symptoms in the days after.

User perceptions of the benefits and harms of hallucinogenic drug use: A web-based questionnaire study

2010| Carhart-Harris, R. L., Nutt, D. J.

This survey study (n=626) investigated user perceptions of the benefits and harms of using LSD, psilocybin, MDMA, cannabis, ketamine, and alcohol. Overall, LSD and psilocybin were regarded as having the most positive impact on wellbeing, and the least harms in terms of physical and mental health.

Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing

2021| Balaet, M., Buchborn, T., Carhart-Harris, R. L., Erritzoe, D., Kaertner, L. S., Kettner, H., Roseman, L., Spriggs, M. J., Steinborn, M. B., Timmermann, C.

This prospective survey study (n=81) found that expectancy effects were mostly predictive of microdosing outcomes on reductions in state anxiety, depressive symptoms (at 4-week endpoint), and positive outcomes (e.g. psychological resilience, -connectedness, -flexibility).

Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

2021| Ances, B. M., Farber, N. B., Kharash, E. D., Lenze, E. J., Nicol, G. E., Palanca, B. J. A., Schweiger, J. A., Siegel, J. S., Snyder, A. Z., Yingling, M. D.

This open-label study (n=23) found that a long (96 hours (4 days)) infusion of ketamine (10mg/70kg/h up to 42mg/70kg/h) significantly improved depressive symptoms (MADRS) for those suffering from treatment-resistant depression. This effect held up to two weeks later and the study also reported on the associated neurobiological changes.

Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial

2012| Brutsche, N. E., Cravchik, A., Diazgranados, N., Franco-Chaves, J., Ibrahim, L., Liberty, V., Luckenbaugh, D. A., Marquardt, C. A., Selter, J., Zarate, C. A.

This double-blind, randomized, crossover, placebo-controlled replication study (n=15) investigated the effects of ketamine (35mg) on patients with treatment-resistant bipolar depression, and found rapid improvements of depressive symptoms, suicidal ideation, and subjective well-being within 40 minutes after infusion and up to 3 days after.

The peak experience variable in DPT-assisted psychotherapy with cancer patients

2012| Dileo, F. B., Rhead, J. C., Richards, W. A., Yensen, R.

This study (1977; n = 34) found that peak experiences may be an important factor in determining the efficacy of DPT-assisted psychotherapy for cancer patients.

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

2015| Crippa, J. A., de Araujo, D. B., Dos Santos, R. G., Hallak, J. E., Macedo, L., Maia-de-Oliveira, J. P., Osório, F. L., Riba, J., Sanches, R. F., Wichert-Ana, L.

This open-label study (n=6) found that a single dose of ayahuasca has fast-acting anxiolytic and antidepressant effects (up to 21 days later, MADRS) in patients with a current depressive episode.

Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression

2018| Ashton, M., Carhart-Harris, R. L., Carrillo, F., Fernández Slezak, D., Fitzgerald, L., Nutt, D. J., Sigman, M., Stroud, J.

This machine-learning study (n=17) was able to predict the therapeutic effectiveness of psilocybin for treatment-resistant depression using an algorithm applied to natural speech data from the baseline interviews. The results were 85% accurate and 75% precise.

Attenuation and anticipation: A therapeutic use of lysergic acid diethylamide

1972| Kast, E.

This open-label clinical study (n=128) investigated whether LSD (100μg) can alleviate death-anxiety in terminally ill patients by decreasing the anticipation of their illness, and found that the administration of LSD was universally well tolerated. Specific effects included a general lift of mood that lasted for 11-12 hours, acute pain relief that lasted 12 hours, decreased the total pain intensity for 3 weeks, and diminished concern over the anticipation of death for up to 3 days after administration.

Individual Experiences in Four Cancer Patients Following Psilocybin-Assisted Psychotherapy

2018| Agin-Liebes, G. I., Belser, A. B., Bogenschutz, M. P., Bossis, A. P., Guss, J., Malone, T., Mennenga, S. E., Owens, L. T., Podrebarac, S. K., Ross, S.

This case study describes patients (n=4) from a randomized, double-blind, placebo-controlled trial investigating single-dose psilocybin (21mg/70kg) psychotherapy to treat cancer-related anxiety and depression. These four participants’ personal narratives extended beyond the cancer diagnosis itself, frequently revolving around themes of self-compassion and love, acceptance of death, and memories of past trauma.

Longterm effects of ayahuasca in patients with recurrent depression: a 5-year qualitative follow-up

2018| Dos Santos, R. G., Hallak, J. E., Osório, F. L.

This qualitative follow-up study (n=8) interviewed patients 4-7 years after the intake of ayahuasca (123.2 mg DMT, 32.34mg Harmine) within the context of a previous open-label study; most patients reported that the experience was among the most important of their lives, but no long-term improvements in depression scores (MADRS) were found.

Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale psychiatric hospital

2018| Katz, R. B., Ostroff, R. B., Sanacora, G., Toprak, M., Webler, R., Wilkinson, S. T.

This clinical study (n=54) found that ketamine was well tolerated as a treatment for depression, although anti-depressant effects were smaller than in previous studies.

DARK Classics in Chemical Neuroscience: Ibogaine

2018| Surratt, C. K., Wasko, M. J., Witt-Enderby, P. A.

This literature review (2018) of the history of ibogaine looks back at the early use, pharmacological studies, and subsequent clinical trials that investigate this compound for the treatment of mental health disorders.

The use of the psychological flexibility model to support psychedelic assisted therapy

2019| Luoma, J. B., Watts, R.

This theory-building paper (2020) presents the ACE (Accept, Connect, Embody) model and how it's being used in a trial (Psilodep 2) with psilocybin-assisted therapy for depression.

Ketamine treatment for individuals with treatment-resistant depression: longitudinal qualitative interview study of patient experiences

2020| Brand, F., Hawton, K., Lascelles, K., Marzano, L., McShane, R., Trueman, H.

This longitudinal interview study (n=12) examined the subjective expectations and effects of ketamine treatment (35mg/70kg) in a population with treatment-resistant depression (TRD). The study found high expectations, side-effects for most (11/12), a reduction in suicidal ideation (SI) for many (8/12) but for some (3/12) more SI when treatment effects decreased (1 week later).

Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors

2020| Campbell, D., Deng, C., Hay, J., Malpas, G., Maxwell, E., McMillan, R., Muthukumaraswamy, S., Ponton, R., Spriggs, M. J., Sumner, R. L., Sundram, F.

This EEG study (n=30) in patients with depression shows that prediction error sensitivity (a possible proxy for brain plasticity, lacking in this population) is improved by ketamine (30.8mg/70kg).

Effects of psilocybin therapy on personality structure

2018| Carhart-Harris, R. L., Erritzoe, D., Kaelen, M., MacLean, K. A., Nour, M. R., Nutt, D. J., Roseman, L.

This open-label study (n=20) found that dosages of psilocybin (10, 25mg) in a supportive setting, for those with treatment-resistant depression (TRD), changed their personality. At 3-month follow-up, Neuroticism was decreased, Extraversion and Openness were increased. The changes were similar (but more pronounced) to changes after conventional antidepressant treatment.

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

2020| Barrett, F. S., Cosimano, M. P., Davis, A. K., Finan, P. H., Griffiths, R. R., Johnson, M. W., May, D. G., Sepeda, N. D.

This randomized open-label study (n=24) found that two sessions with psilocybin (20 and 30mg/70kg) significantly improved depression scores for a population with major depressive disorder (MDD) up to 8 weeks later.

Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial

2018| Burke, A. K., Choo, T-H., Galfalvy, H. C., Grunebaum, M. F., Keilp, J. G., Mann, J. J., Marver, J. E., Milak, M. S., Moitra, V. K., Oquendo, M. A., Parris, M. S., Sublette, M. E.

This randomized study (n=80) found that participants with depression (MDD) and suicidal ideation (SSI/SI) who were treated with ketamine (IV, 35mg/70kg) have significantly lower SSI scores versus treatment with midazolam (another anesthetic). This effect consistently held up to 6 weeks later.

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

2018| Alchieri, J. C., Andrade, K. C., Araújo, D. B., Arcoverde, E., Barreto, D., De Oliveira Silveira, G., Dos Santos, R. G., Galvão-Coelho, N. L., Hallak, J. E., Lobão-Soares, B., Maia-de-Oliveira, J. P., Mota-Rolim, S. A., Novaes, M. M., Onias, H., Osório, F. L., Palhano-Fontes, F., Pessoa, J. A., Riba, J., Santos, F. R., Silva-Junior, A. A., Tófoli, L.F., Yonamine, M.

This randomized placebo-controlled trial investigated the antidepressant efficacy of ayahuasca (25.2mg/70kg DMT, 130.2mg/70kg harmine, 16.8mg/70kg harmaline, 84mg/70kg tetrahydroharmine) in patients with depression. While both groups exhibited improvements in depression, between-group effect sizes increased throughout the week, yielding a significantly higher response rate in the ayahuasca group after a week.

Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression

2020| Carhart-Harris, R. L., Demetriou, L., Mertens, L. J., Nutt, D. J., Roseman, L., Wall, M. B.

This further analysis of an fMRI study (n=19) investigated changes in brain function before versus after psilocybin (with psychological support) in patients with depression (TRD). After treatment, patients showed changes in amygdala function connectivity.

Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial

2020| de Lima Osório, F., Dos Santos, R. G., Hallak, J. E., Sanches, R. F., Weissman, C. R., Zeifman, R. J.

This analysis of an earlier open-label study (n=15) on Ayahuasca, found significant (Hedges' g = 1.75) and sustained decreases in suicidality in people with depression (MDD).

Post-Psychedelic Reductions in Experiential Avoidance Are Associated With Decreases in Depression Severity and Suicidal Ideation

2020| Carhart-Harris, R. L., Kettner, H., Mertens, L. J., Wagner, A. C., Watts, R., Zeifman, R. J.

A prospective survey study (n=358) found that psychedelics may lead to significant decreases in experiential avoidance, depression severity, and suicidal ideation.

Patients’ accounts of increased connectedness and acceptance after psilocybin for treatment-resistant depression

2017| Carhart-Harris, R. L., Day, C. M., Krzanowski, J., Nutt, D. J., Watts, R.

This follow-up survey to an open-label study (n=20) on psilocybin for treatment-resistant depression (TRD) found that connection (vs disconnection) and acceptance (vs avoidance) of emotions were the two main mechanisms through which the therapy was successful.

Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

2019| Christiansen, S. L., Elfving, B., Højgaard, K., Jefsen, O., Müller, H. K., Nutt, D. J., Wegener, G.

This rat-model study (Flinders Sensitive Line - depressed rats) found no anti-depressant effects when given psilocybin (or psilocin). This study shows that a rat-model study may not be a good model for studying depression and psychedelics/psilocybin.

Comparison of Rapid Antidepressant and Antisuicidal Effects of Intramuscular Ketamine, Oral Ketamine, and Electroconvulsive Therapy in Patients With Major Depressive Disorder

2020| Kheirabadi, D., Kheirabadi, G. R., Mirlohi, Z., Norbaksh, A., Tarrahi, M. J.

This pilot study (n=45) found that oral and IV ketamine was as effective as electroconvulsive therapy (ECT) for depression (MDD) and suicidal ideation, and was rated more positively by participants.

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

2017| Bolstridge, M., Carhart-Harris, R. L., Curran, H. V., Demetriou, L., Kaelen, M., Leech, R., McGonigle, J., Murphy, K., Nutt, D. J., Pannekoek, J. N., Roseman, L., Tanner, M., Wall, M. B.

This within-subjects fMRI study (n=19) investigated changes in brain function before versus after psilocybin (with psychological support) in patients with treatment-resistant depression. After treatment, all patients showed decreased depressive symptoms and changes in brain functioning.

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression a SPECT study

2016| Araújo, D. B., Crippa, J. A., Dos Santos, R. G., Hallak, J. E., Macedo, L., Maia-de-Oliveira, J. P., Osório, F. L., Riba, J., Sanches, R. F., Wichert-Ana, L.

This open-label study (n=17) found that a single-dose of Ayahausca had significant effects antidepressant effects up to 21 days later (MADRS-scale and others).

Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors

2020| Bachmann, R., Kometer, M., Schmidt, A., Seifritz, E., Studerus, E., Vollenweider, F. X.

In this double-blind, within-subjects, placebo-controlled study (n=17) it was investigated whether psilocybin does bias emotional processing away from negative information by activating 5-HT2A (Serotonin) receptors. It was indeed found that psilocybin enhanced mood and shifted emotional bias towards positive information. The 5-HT2A receptors played a crucial roll in the effects of psilocybin on emotional processing.

Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression

2017| Carhart-Harris, R. L., Curran, H. V., Freeman, T. P., Hindocha, C., Lawn, W., Leech, R., Nutt, D. J., Stroud, J.

This between-subjects study (n=33) investigated whether psilocybin alters emotional processing biases in patients with treatment-resistant depression (TRD) when compared to healthy controls without TRD or psilocybin use. Two sessions of psilocybin with psychological support did improve the processing of emotional faces in treatment-resistant depression and this correlated with reduced anhedonia.

Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression

2018| Carhart-Harris, R. L., Nutt, D. J., Roseman, L.

This open-label study (n=20) found that the quality of the psychedelic experience (10-25mg psilocybin, measured with the ASC - specifically oceanic boundlessness) predicted therapeutic effect (lower depression scores).

Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety

2020| Barrett, F. S., Davis, A. K., Griffiths, R. R.

This survey study (n=985) finds that psychological flexibility fully mediated the effects of mystical/peak experiences on depression/anxiety.

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

2017| Bloomfield, M., Bolstridge, M., Carhart-Harris, R. L., Curran, H. V., Day, C. M., Erritzoe, D., Feilding, A., Forbes, B., Giribaldi, B., Kaelen, M., Nutt, D. J., Pilling, S., Rickard, J. A., Rucker, J., Taylor, D., Watts, R.

This open-label study (n=20) expands on earlier work by Carhart-Harris and colleagues on the use of psilocybin-assisted therapy for treatment-resistant depression (TRD).

Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer

2010| Chopra, G. S., Danforth, A. L., Greer, G. R., Grob, C. S., Hagerty, M., Halberstadt, A. L., McKay, C. R.

This is the first (modern) double-blind placebo-controlled study (n=12) of psilocybin (14mg/70kg) for the treatment of (end-of-life) anxiety (and depression) related to cancer.

Perceived outcomes of psychedelic microdosing as self-managed therapies for mental and substance use disorders

2020| Amanda, N., Jungaberle, H., Lea, T., Schecke, H., Scherbaum, N.

This survey (n=1102) study found positive effects after microdosing psychedelics (44% reported 'much better' mental health), but was limited to self-reports.

Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

2020| Amoroso, T., Averill, L. A., Barsuglia, J. P., Davis, A. K., Sepeda, N. D.

This survey study (n=51) found very large effects on mental health for special forces veterans after ibogaine and 5-MeO-DMT treatment.

Patient Experiences of Psilocybin-Assisted Psychotherapy: An Interpretative Phenomenological Analysis

2017| Agin-Liebes, G. I., Belser, A. B., Bossis, A. P., Devenot, N., Friedman, H. L., Guss, J., Ross, S., Swift, T. C.

This qualitative analysis of experiences may help form new hypotheses on why a psychedelic experience works. Found is that participants experienced strong emotions, partly conveyed by music.

Increased nature relatedness and decreased authoritarian political views after psilocybin for treatment-resistant depression

2018| Carhart-Harris, R. L., Lyons, T.

A pilot study (n=14) on how psychedelics increase nature relatedness and decrease authoritarianism. Although the active participants (n=7, with treatment-resistant depression) increased on both, their final scores on those measures were very similar to that of the non-treated (non-depressed) group.

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

2016| Griffiths, R. R., Johnson, M. W.

This study investigated the effects of a high dose of psilocybin on depression and anxiety in patients with life-threatening cancer. It found significant improvements, even without psychotherapy (as many other studies do provide).

Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression

2017| Carhart-Harris, R. L., Demetriou, L., Nutt, D. J., Roseman, L., Wall, M. B.

Psychedelics work differently than SSRIs and are hypothesized to treat the underlying disconnect with emotions, getting someone in touch with them again. This analysis of an open-label study (n=20) supports this argument with fMRI studies that showed increased amygdala responses to emotional stimuli.

Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

2016| Bloomfield, M., Bolstridge, M., Carhart-Harris, R. L., Curran, H. V., Day, C. M., Feilding, A., Forbes, B., Kaelen, M., Nutt, D. J., Pilling, S., Rickard, J. A., Rucker, J., Taylor, D.

This is the first modern study (n=12) on psilocybin and its effects on treatment-resistant depression. It shows that two sessions with psilocybin (10mg and 25mg) in combination with psychological support can reduce depressive symptoms over periods of one week to three months after treatment. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred.

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial

2016| Agin-Liebes, G. I., Babb, J., Belser, A. B., Bossis, A. P., Cohen, B., Corby, P., Guss, J., Kalliontzi, K., Malone, T., Mennenga, S. E., Ross, S., Schmidt, B. L., Su, Z.

This double-blind placebo-controlled study (n=29) for those suffering from anxiety and depression, related to cancer, improved significantly (60-80% of participants) after a single dose of psilocybin (21mg/70kg) in combination with psychotherapy.

Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer

2020| Agin-Liebes, G. I., Bossis, A. P., Fischer, S., Grigsby, J., Guss, J., Malone, T., Mennenga, S. E., Ponté, K. L., Ross, S., Yalch, M. M.

This is a follow-up study (n=16) at an average of 3.8 years after a single dose of psilocybin, in combination with psychotherapy, for patients suffering from existential distress related to cancer. Approximately 60-80% of participants still experienced reduced anxiety or depressive symptoms. This adds to the body of research that indicates that the positive of a guided psychedelic experience can be long-lasting.


This section compares the research with psychedelics to other therapies, medicines, or treatments.


This section highlights the various measures used and their use in research.


Who are the top researches in this area, the ones who have done the groundbreaking research.


What do we not know at this time? Where are the gaps in our knowledge and are we closing it?


The companies that are actively engaged in researching this topic or (planning to) provide therapy focussed on this topic.

Outside Academia

This section highlights everything done outside of academia, from popular press to books and non academic research.